Liver Disease

ABSTRACT

Methods of treating a liver disease or condition, or a symptom thereof, in a subject in need of treatment, are disclosed and described. One method comprises orally administering to a subject, a pharmaceutical composition having an amount of a testosterone, or an ester thereof, sufficient to treat the liver disease or condition, or symptom thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This nonprovisional utility patent application is a continuation of andclaims the benefit under 35 USC § 120 to co-pending U.S. applicationSer. No. 16/554,444 filed Aug. 28, 2019, which is a continuation of andclaims the benefit under 35 USC § 120 to co-pending U.S. applicationSer. No. 16/517,533 filed Jul. 19, 2019, which claims the benefit under35 USC § 119(e) of US provisional application Nos. 62/701,309, filedJul. 20, 2018; 62/714,968 filed Aug. 6, 2018; 62/728,580 filed Sep. 7,2018; 62/783,190, filed Dec. 20, 2018; and 62/793,724, filed Jan. 17,2019, all of which are expressly incorporated herein in their entiretyby this reference.

FIELD OF THE INVENTION

This disclosure relates to compositions and methods for treating liverdisease and reducing mortality in specific patient populations.

BACKGROUND

Historically, some androgens like anabolic-androgenic compounds wereconsidered to have toxic effects on the liver. See e.g., Bond et al.PMID: 27372877; Neri et al. PMID: 21443508; and Kemp C J et al. PMID:2798421.

Despite evidence of hepatotoxicity of androgens in the literature,studies have examined the effect of testosterone on liver fat reductionin fatty liver disease and have general reported inconclusive ornegative results in humans. For example, Huang et al. (PMID: 23292288)concluded “Testosterone administration in older men with mobilitylimitation and low testosterone levels was not associated with areduction in hepatic fat.” Moreover, elevated testosterone levels infemales can associated with fatty liver, liver disease and relatedcomorbidities. Magnussen et al PMID: 28522646 reported “hepatic fatcontent and VAT were unchanged” in males with type 2 diabetes and lowtestosterone levels that were treated for 24-weeks with a testosteronegel. Sattler et al PMID: 25392748 also reported that testosteronereplacement did not have an effect of liver fat in 20 men with lowerbaseline levels of testosterone when treated for 20 weeks with atestosterone gel.

There is a need for testosterone/androgen based therapies for specificpopulations of individuals. More specifically, there is a need for newtherapies for liver disease.

SUMMARY

Described herein are methods and composition for use in treating,preventing, slowing the progression, or reducing the risk of liverdisease (or comorbidities thereof) or symptoms thereof. In particular,it was discovered that androgen receptor modulators e.g., agonists areuseful for improving liver function, liver diseases or conditions andrelated comorbidities. While a number of modalities for treating liverdisease are described herein in the context of oral androgen therapye.g., oral administration of testosterone esters like testosteroneundecanoate, the skilled artisan recognizes in view of this disclosure,other androgen receptor agonist can be adapted and employed in thesemethods such as transdermal, nasal, buccal, and injectable testosteroneproducts. In addition to testosterone, testosterone esters and the such,other androgen receptor agonists may be employed herein as well asmethods and compounds, pharmaceuticals, nutritional or vitaminsupplements that increase serum testosterone levels, serum freetestosterone levels, or androgen receptor signaling in target tissues orcompartments.

It was surprisingly discovered that oral testosterone (or androgen)therapy e.g., oral administration of a pharmaceutical compositioncontaining a testosterone ester (e.g., or an androgen receptor agonistor anabolic agent), is particularly useful for treating liver disease.For example, it was found that the instant methods and compositionsreduce relevant biomarker levels in patients having elevated biomarkersrelated to liver disease (e.g., fatty liver disease, liver fibrosis,alcoholic liver disease, hepatitis, steatosis, NAFLD, NASH, NASH withcirrhosis, and comorbidities of testosterone deficiency). Unexpectedly,the methods and compositions disclosed herein, demonstrated a reductionin serum alkaline phosphatase levels that was significantly better thanthat observed with a once a day topical testosterone product (e.g,ANDROGEL™), a marketed testosterone replacement therapy administered viathe transdermal route. Other unexpected findings include substantialreductions (or improvements) in triglyceride levels, biomarkers of liverinjury, and biomarkers for other diseases and conditions (e.g.,lipoprotein-associated phospholipase A2), a biomarker of cardiovasculardisease. Thus, in one implementation, the methods described hereinincrease the ratio of serum testosterone levels to alkaline phosphatase(e.g., by 5%, 10%, 15%, 20%, or 25% or more). In another implementationthe methods described herein increase the ratio of serum testosteronelevels to serum triglyceride levels (e.g., by 5%, 10%, 15%, 20%, or 25%or more). In other implementations, the methods and compositionsdisclosed herein, improve diseases and conditions (or symptoms orrelated biomarkers) in conditions that are co-morbid with lowtestosterone levels (e.g., either total testosterone or freetestosterone).

Without wishing to be bound by theory, it is believed that in somecontexts, as illustrated herein, testosterone deficient subjects withspecific biomarkers in the high normal range or above normal areparticularly sensitive to the methods and compositions described hereinand see surprising reductions or improvements in the levels of thesebiomarkers. Again, in many cases these biomarker improvements are bothover baseline values and in comparison to an active control (transdermaltestosterone preparation). Moreover, populations of individuals that areat higher risk for developing specific diseases and conditions areparticularly amenable to the treatments described herein (includingthose that do not have testosterone deficiency). Thus, the methods andcompositions described herein improve or ameliorate biomarkersassociated with diseases by 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%,or 70% or more compared to baseline values. It is also believed that themethod and compositions described herein have utility and can be used insubjects that do not have testosterone deficiency.

It was unexpectedly found that normalization or improvement ofbiomarkers (e.g., one or more biomarkers) can occur relatively quicklyafter commencement of the methods using the compositions describedherein. For example, treatment for 1, 2, 3, 4, 5, 6, or 7 or more weekscan provide substantial improvements in one or more biomarkersassociated with liver disease or mortality. Moreover, the methods andcompositions provide sustained responses e.g., 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11 or 12 months or more. As illustrated in the Examples,treatment with the methods and compositions described herein for 3 weekscan result in substantial improvements of biomarker levels. Typically,the treatments described herein are once-a-day or twice-a-day dosingregimens, although other dosing regimens are contemplated and have beenshown to be effective e.g., three times a day. It is also notable thatboth testosterone undecanoate based oral dosing regimens andtestosterone tridecanoate dosing regimens are effective in thesetreatments. Thus, without wishing to be bound by theory, it is believedthat the methods and compositions described herein can be used withnumerous testosterone esters and other steroid (and steroid estercontaining compositions). For example, the methods and compositionsdescribed herein can be used with testosterone esters wherein the estermoiety can have from 2-20 carbons (e.g., the ester moiety is derivedfrom a 2 carbon to 20 carbon fatty acid or fatty acid derivativeincluding straight chain, branched chain, cyclic (e.g., cypionate orcypionic acid), saturated, and unsaturated (oleate or oleic acid)versions of 2 carbon to 20 carbon alkanoic acids). Thus, thecompositions including two or more testosterone esters (e.g.,testosterone undecanoate and testosterone tridecanoate) can be useful inthe methods disclosed herein and have unexpected effects.

Provided herein are methods and compositions useful for treatingconditions associated with increased mortality such as liver disease andparticularly fatty liver disease, non-alcoholic fatty liver disease,non-alcoholic steatohepatitis, steatosis, cirrhosis, alcoholic liverdisease and other liver diseases. Moreover, provided herein are methodsfor treating liver disease or a symptom thereof. Furthermore, providedherein are compositions and methods for modulating biomarkers associatedwith liver disease or symptoms thereof.

Accordingly, in one embodiment, a method of treating a liver disease orcondition is provided, said method comprising identifying a subject inneed of treatment e.g., has a liver disease or condition. In one aspect,said method comprises oral administration of 200 mg to 750 mg oftestosterone undecanoate per day to a male subject (e.g., in need oftreatment). In one aspect, said method comprises oral administration of300 mg to 600 mg of testosterone undecanoate per day to a male subject.In one aspect, said method comprises oral administration of 450 mg oftestosterone undecanoate per day to a male subject. In one aspect, saidmethod comprises oral administration of about 400 mg to 2000 mg oftestosterone tridecanoate per day to a male subject. In one aspect, saidmethod comprises oral administration of about 600 mg to 1800 mg oftestosterone tridecanoate per day to a male subject. In one aspect, saidmethod comprises oral administration of about 500 mg, 750 mg, 1000 mg,or 1250 mg of testosterone tridecanoate per day to a male subject. Thesedose ranges are typically those for male subjects whereas the femaledose range corresponds to about 1/10^(th)- 1/15^(th) of these values. Inone aspect, the subject is from 1 to 18 years old, 18-25 years old,26-35 years old, 36-45 years old, 45-55 years old, 56-65 years old orolder than 65 years old. In one aspect, said subject (e.g., in need oftreatment) has a disease or condition chosen from metabolic syndrome,diabetes (e.g., Type 2 Diabetes), hypertension, obesity, hypogonadism,hypertriglyceridemia, fatty liver disease, liver fibrosis, steatosis,cirrhosis, hepatitis, cardiovascular disease, NASH (“Non-AlcoholicSteatoHepatitis”), NAFLD (“Non-Alcoholic Fatty Liver Disease”), primarysclerosing cholangitis, is waiting for a liver transplant, has receiveda liver transplant, primary biliary cholangitis, a liver disease orcondition associated with chronic inflammation, hepatocellularcarcinoma, graft versus host disease e.g., related to liver transplant,an autoimmune disease related to the liver (or has a biomarker levelrelated to or indicative of one or more of these diseases). In oneaspect, said method comprises identifying a subject in need oftreatment. In one aspect, the disease or condition is a comorbidity oftestosterone deficiency. In a specific aspect, the subject in need oftreatment is treated with one or more additional therapeutic agents(e.g., combination therapy). Additionally, this paragraph is to be readas being specifically incorporated into each specific method or methodembodiment described in the Detailed Description.

Accordingly, in one embodiment, a method of treating a liver disease orcondition is provided, said method comprising identifying a subject witha biomarker associated with said liver disease or condition where thebiomarker is in the upper normal range and orally administering to saidsubject a pharmaceutical composition comprising a testosterone ester(e.g., testosterone undecanoate or testosterone tridecanoate) in anamount sufficient to reduce the level of the biomarker or reduce therate of increase of the biomarker. In one aspect of this method, thesubject has testosterone deficiency. In one aspect, said subject in needof treatment has testosterone deficiency with serum testosterone levelsof less than 350 ng/dL, 300 ng/dL, 250 ng/dL, 200 ng/dL, 150 ng/dL or100 ng/dL for a male subject or 1/10^(th) of these values for a femalesubject. In one aspect, said method comprise oral administration of 200mg to 750 mg of testosterone undecanoate per day to a male subject. Inone aspect, said method comprises oral administration of 300 mg to 600mg of testosterone undecanoate per day to a male subject. In one aspect,said method comprise oral administration of 450 mg of testosteroneundecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of about 400 mg to 2000 mg of testosteronetridecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of about 600 mg to 1800 mg of testosteronetridecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of about 500 mg, 750 mg, 1000 mg, or 1250mg of testosterone tridecanoate per day to a male subject. These doseranges are typically those for male subjects whereas the female doserange corresponds to about 1/10^(th)- 1/15^(th) of these values. In oneaspect the subject is from 18-25 years old, 26-35 years old, 36-45 yearsold, 45-55 years old, 56-65 years old or older than 65 years old. In oneaspect, said subject (e.g., in need of treatment) has a disease orcondition chosen from metabolic syndrome, diabetes (e.g., Type 2Diabetes), hypertension, obesity, hypogonadism, hypertriglyceridemia,fatty liver disease, liver fibrosis, steatosis, cirrhosis, hepatitis,cardiovascular disease, NASH, NAFLD, primary sclerosing cholangitis, iswaiting for a liver transplant, has received a liver transplant, primarybiliary cholangitis, a liver disease or condition associated withchronic inflammation, hepatocellular carcinoma, graft versus hostdisease e.g., related to liver transplant, an autoimmune disease relatedto the liver (or has a biomarker level related to or indicative of oneor more of these diseases). In one aspect, said method comprisesidentifying a subject in need of treatment. In one aspect, the diseaseor condition is a comorbidity of testosterone deficiency. In a specificaspect, the subject in need of treatment is treated with one or moreadditional therapeutic agents (e.g., combination therapy). Additionally,this paragraph is to be read as being specifically incorporated intoeach specific method or method embodiment described in the DetailedDescription.

Accordingly, in one embodiment, a method of treating a liver disease orcondition is provided, said method comprising identifying a subject witha biomarker associated with said disease or condition where thebiomarker is outside of the normal range (e.g., above or below) andorally administering to said subject a pharmaceutical compositioncomprising a testosterone ester (e.g., testosterone undecanoate ortestosterone tridecanoate) in an amount sufficient to ameliorate orimprove the level of the biomarker (e.g., move the level in thedirection of the normal range), reduce the rate of increase or decreaseof the biomarker, or treat the disease or condition. In one aspect ofthis method, the subject has testosterone deficiency. In one aspect,said subject in need of treatment has testosterone deficiency with serumtestosterone levels of less than 350 ng/dL, 300 ng/dL, 250 ng/dL, 200ng/dL, 150 ng/dL or 100 ng/dL for a male subject or 1/10^(th) of thesevalues for a female subject. In one aspect, said method comprises oraladministration of 200 mg to 750 mg of testosterone undecanoate per dayto a male subject. In one aspect, said method comprises oraladministration of 300 mg to 600 mg of testosterone undecanoate per dayto a male subject. In one aspect, said method comprises oraladministration of 450 mg of testosterone undecanoate per day to a malesubject. In one aspect, said method comprises oral administration ofabout 400 mg to 2000 mg of testosterone tridecanoate per day to a malesubject. In one aspect, said method comprises oral administration ofabout 600 mg to 1800 mg of testosterone tridecanoate per day to a malesubject. In one aspect, said method comprises oral administration ofabout 500 mg, 750 mg, 1000 mg, or 1250 mg of testosterone tridecanoateper day to a male subject. These dose ranges are typically those formale subjects whereas the female dose range corresponds to about1/10^(th)- 1/15^(th) of these values. In one aspect the subject is from18-25 years old, 26-35 years old, 36-45 years old, 45-55 years old,56-65 years old or older than 65 years old. In one aspect, said subject(e.g., in need of treatment) has a disease or condition chosen frommetabolic syndrome, diabetes (e.g., Type 2 Diabetes), hypertension,obesity, hypogonadism, hypertriglyceridemia, fatty liver disease, liverfibrosis, steatosis, cirrhosis, hepatitis, cardiovascular disease, NASH,NAFLD, primary sclerosing cholangitis, is waiting for a livertransplant, has received a liver transplant, primary biliarycholangitis, a liver disease or condition associated with chronicinflammation, hepatocellular carcinoma, graft versus host disease e.g.,related to liver transplant, an autoimmune disease related to the liver(or has a biomarker level related to or indicative of one or more ofthese diseases). In one aspect, said method comprises identifying asubject in need of treatment. In one aspect, the disease or condition isa comorbidity of testosterone deficiency. In a specific aspect, thesubject in need of treatment is treated with one or more additionaltherapeutic agents (e.g., combination therapy). Additionally, thisparagraph is to be read as being specifically incorporated into eachspecific method or method embodiment described in the DetailedDescription.

Accordingly, in yet another embodiment, a method of treating a liverdisease or condition is provided, said method comprising identifying asubject with a biomarker associated with said disease or condition wherethe biomarker is above the upper normal limit and orally administeringto said subject a pharmaceutical composition comprising a testosteroneester (e.g., testosterone undecanoate or testosterone tridecanoate) inan amount sufficient to reduce the level of the biomarker or reduce therate of increase of the biomarker. In one aspect of this method, thesubject has testosterone deficiency. In one aspect, said subject in needof treatment has testosterone deficiency with serum testosterone levelsof less than 350 ng/dL, 300 ng/dL, 250 ng/dL, 200 ng/dL, 150 ng/dL or100 ng/dL for a male subject or 1/10^(th) of these values for a femalesubject. In one aspect, said method comprises oral administration of 200mg to 750 mg of testosterone undecanoate per day to a male subject. Inone aspect, said method comprises oral administration of 300 mg to 600mg of testosterone undecanoate per day to a male subject. In one aspect,said method comprises oral administration of 450 mg of testosteroneundecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of about 400 mg to 2000 mg of testosteronetridecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of about 600 mg to 1800 mg of testosteronetridecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of about 500 mg, 750 mg, 1000 mg, or 1250mg of testosterone tridecanoate per day to a male subject. These doseranges are typically those for male subjects whereas the female doserange corresponds to about 1/10^(th)- 1/15^(th) of these values. In oneaspect, the subject is from 18-25 years old, 26-35 years old, 36-45years old, 45-55 years old, 56-65 years old or older than 65 years old.In one aspect, said subject (e.g., in need of treatment) has a diseaseor condition chosen from metabolic syndrome, diabetes (e.g., Type 2Diabetes), hypertension, obesity, hypogonadism, hypertriglyceridemia,fatty liver disease, liver fibrosis, steatosis, cirrhosis, hepatitis,cardiovascular disease, NASH, NAFLD, primary sclerosing cholangitis, iswaiting for a liver transplant, has received a liver transplant, primarybiliary cholangitis, a liver disease or condition associated withchronic inflammation, hepatocellular carcinoma, graft versus hostdisease e.g., related to liver transplant, an autoimmune disease relatedto the liver (or has a biomarker level related to or indicative of oneor more of these diseases). In one aspect, said method comprisesidentifying a subject in need of treatment. In one aspect, the diseaseor condition is a comorbidity of testosterone deficiency. In a specificaspect, the subject in need of treatment is treated with one or moreadditional therapeutic agents (e.g., combination therapy). Additionally,this paragraph is to be read as being specific incorporated into eachspecific method or method embodiment described in the DetailedDescription.

Accordingly, in one embodiment, a method of treating a disease orcondition is provided, said method comprising identifying a subject witha biomarker associated with said disease or condition where thebiomarker is above twice the upper normal range limit and orallyadministering to said subject a pharmaceutical composition comprising atestosterone ester (e.g., testosterone undecanoate or testosteronetridecanoate) in an amount sufficient to reduce the level of thebiomarker or reduce the rate of increase of the biomarker. In oneaspect, said subject in need of treatment has testosterone deficiencywith serum testosterone levels of less than 350 ng/dL, 300 ng/dL, 250ng/dL, 200 ng/dL, 150 ng/dL or 100 ng/dL for a male subject or 1/10th ofthese values for a female subject. In one aspect, said method comprisesoral administration of 200 mg to 750 mg of testosterone undecanoate perday to a male subject. In one aspect, said method comprises oraladministration of 300 mg to 600 mg of testosterone undecanoate per dayto a male subject. In one aspect, said method comprises oraladministration of 450 mg of testosterone undecanoate per day to a malesubject. In one aspect, said method comprises oral administration ofabout 400 mg to 2000 mg of testosterone tridecanoate per day to a malesubject. In one aspect, said method comprises oral administration ofabout 600 mg to 1800 mg of testosterone tridecanoate per day to a malesubject. In one aspect, said method comprises oral administration ofabout 500 mg, 750 mg, 1000 mg, or 1250 mg of testosterone tridecanoateper day to a male subject. These dose ranges are typically those formale subjects whereas the female dose range corresponds to about1/10^(th)- 1/15^(th) of these values. In one aspect, the subject is from18-25 years old, 26-35 years old, 36-45 years old, 45-55 years old,56-65 years old or older than 65 years old. In one aspect, said subject(e.g., in need of treatment) has a disease or condition chosen frommetabolic syndrome, diabetes (e.g., Type 2 Diabetes), hypertension,obesity, hypogonadism, hypertriglyceridemia, fatty liver disease, liverfibrosis, steatosis, cirrhosis, hepatitis, cardiovascular disease, NASH,NAFLD, primary sclerosing cholangitis, is waiting for a livertransplant, has received a liver transplant, primary biliarycholangitis, a liver disease or condition associated with chronicinflammation, hepatocellular carcinoma, graft versus host disease e.g.,related to liver transplant, an autoimmune disease related to the liver(or has a biomarker level related to or indicative of one or more ofthese diseases). In one aspect, said method comprises identifying asubject in need of treatment. In one aspect, the disease or condition isa comorbidity of testosterone deficiency. In a specific aspect, thesubject in need of treatment is treated with one or more additionaltherapeutic agents (e.g., combination therapy). Additionally, thisparagraph is to be read as being specifically incorporated into eachspecific method or method embodiment described in the DetailedDescription.

Accordingly, in one embodiment, a method of treating a liver disease orcondition is provided said method comprising identifying a subject witha biomarker associated with said disease or condition where thebiomarker is above 3 times the upper normal limit and orallyadministering to said subject a pharmaceutical composition comprising atestosterone ester (e.g., testosterone undecanoate or testosteronetridecanoate) in an amount sufficient to reduce the level of thebiomarker or reduce the rate of increase of the biomarker. In one aspectof this method, the subject has testosterone deficiency. In one aspect,said subject in need of treatment has testosterone deficiency with serumtestosterone levels of less than 350 ng/dL, 300 ng/dL, 250 ng/dL, 200ng/dL, 150 ng/dL or 100 ng/dL for a male subject or 1/10^(th) of thesevalues for a female subject. In one aspect, said method comprises oraladministration of 200 mg to 750 mg of testosterone undecanoate per dayto a male subject. In one aspect, said method comprises oraladministration of 300 mg to 600 mg of testosterone undecanoate per dayto a male subject. In one aspect, said method comprise oraladministration of 450 mg of testosterone undecanoate per day to a malesubject. In one aspect, said method comprises oral administration ofabout 400 mg to 2000 mg of testosterone tridecanoate per day to a malesubject. In one aspect, said method comprises oral administration ofabout 600 mg to 1800 mg of testosterone tridecanoate per day to a malesubject. In one aspect, said method comprises oral administration ofabout 500 mg, 750 mg, 1000 mg, or 1250 mg of testosterone tridecanoateper day to a male subject. These dose ranges are typically those formale subjects whereas the female dose range corresponds to about1/10^(th)- 1/15^(th) of these values. In one aspect the subject is from18-25 years old, 26-35 years old, 36-45 years old, 45-55 years old,56-65 years old or older than 65 years old. In one aspect, said subject(e.g., in need of treatment) has a disease or condition chosen frommetabolic syndrome, diabetes (e.g., Type 2 Diabetes), hypertension,obesity, hypogonadism, hypertriglyceridemia, fatty liver disease, liverfibrosis, steatosis, cirrhosis, hepatitis, cardiovascular disease, NASH,NAFLD, primary sclerosing cholangitis, is waiting for a livertransplant, has received a liver transplant, primary biliarycholangitis, a liver disease or condition associated with chronicinflammation, hepatocellular carcinoma, graft versus host disease e.g.,related to liver transplant, an autoimmune disease related to the liver(or has a biomarker level related to or indicative of one or more ofthese diseases). In one aspect, said method comprises identifying asubject in need of treatment. In one aspect, the disease or condition isa comorbidity of testosterone deficiency. In a specific aspect, thesubject in need of treatment is treated with one or more additionaltherapeutic agents (e.g., combination therapy). Additionally, thisparagraph is to be read as being specifically incorporated into eachspecific method or method embodiment described in the DetailedDescription.

Accordingly, in one embodiment, a method of treating a liver disease orcondition is provided, said method comprising identifying a subject witha biomarker associated with said disease or condition where thebiomarker is between the upper normal limit and twice or thrice theupper normal limit, and orally administering to said subject apharmaceutical composition comprising a testosterone ester (e.g.,testosterone undecanoate or testosterone tridecanoate) in an amountsufficient to reduce the level of the biomarker or reduce the rate ofincrease of the biomarker. In one aspect of this method, the subject hastestosterone deficiency. In one aspect, said subject in need oftreatment has testosterone deficiency with serum testosterone levels ofless than 350 ng/dL, 300 ng/dL, 250 ng/dL, 200 ng/dL, 150 ng/dL or 100ng/dL for a male subject or 1/10^(th) of these values for a femalesubject. In one aspect, said method comprises oral administration of 200mg to 750 mg of testosterone undecanoate per day to a male subject. Inone aspect, said method comprises oral administration of 300 mg to 600mg of testosterone undecanoate per day to a male subject. In one aspect,said method comprises oral administration of 450 mg of testosteroneundecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of about 400 mg to 2000 mg of testosteronetridecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of about 600 mg to 1800 mg of testosteronetridecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of about 500 mg, 750 mg, 1000 mg, or 1250mg of testosterone tridecanoate per day to a male subject. These doseranges are typically those for male subjects whereas the female doserange corresponds to about 1/10^(th)- 1/15^(th) of these values. In oneaspect the subject is from 18-25 years old, 26-35 years old, 36-45 yearsold, 45-55 years old, 56-65 years old or older than 65 years old. In oneaspect, said subject (e.g., in need of treatment) has a disease orcondition chosen from metabolic syndrome, diabetes (e.g., Type 2Diabetes), hypertension, obesity, hypogonadism, hypertriglyceridemia,fatty liver disease, liver fibrosis, steatosis, cirrhosis, hepatitis,cardiovascular disease, NASH, NAFLD, primary sclerosing cholangitis, iswaiting for a liver transplant, has received a liver transplant, primarybiliary cholangitis, a liver disease or condition associated withchronic inflammation, hepatocellular carcinoma, graft versus hostdisease e.g., related to liver transplant, an autoimmune disease relatedto the liver (or has a biomarker level related to or indicative of oneor more of these diseases). In one aspect, said method comprisesidentifying a subject in need of treatment. In one aspect, the diseaseor condition is a comorbidity of testosterone deficiency. In a specificaspect, the subject in need of treatment is treated with one or moreadditional therapeutic agents (e.g., combination therapy). Additionally,this paragraph is to be read as being specific incorporated into eachspecific method or method embodiment described in the DetailedDescription.

Accordingly, in one embodiment, a method of treating a liver disease orcondition is provided said method comprising identifying a subject witha biomarker that is greater than the upper normal limit, greater than 2times the upper normal limit, greater than 3 times the upper normallimit, greater than 4 times the upper limit, or defined by any two ofthese bounds (e.g., 3-4 times upper normal limit) associated with saiddisease or condition and orally administering to said subject apharmaceutical composition comprising a testosterone ester (e.g.,testosterone undecanoate or testosterone tridecanoate) in an amountsufficient to reduce the level of the biomarker or reduce the rate ofincrease of the biomarker. In one aspect of this method, the subject hastestosterone deficiency. In one aspect, said subject in need oftreatment has testosterone deficiency with serum testosterone levels ofless than 350 ng/dL, 300 ng/dL, 250 ng/dL, 200 ng/dL, 150 ng/dL or 100ng/dL for a male subject or 1/10 of these values for a female subject.In one aspect, said method comprises oral administration of 200 mg to750 mg of testosterone undecanoate per day to a male subject. In oneaspect, said method comprises oral administration of 300 mg to 600 mg oftestosterone undecanoate per day to a male subject. In one aspect, saidmethod comprises oral administration of 450 mg of testosteroneundecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of about 400 mg to 2000 mg of testosteronetridecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of about 600 mg to 1800 mg of testosteronetridecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of about 500 mg, 750 mg, 1000 mg, or 1250mg of testosterone tridecanoate per day to a male subject. These doseranges are typically those for male subjects whereas the female doserange corresponds to about 1/10^(th)- 1/15^(th) of these values. In oneaspect the subject is from 18-25 years old, 26-35 years old, 36-45 yearsold, 45-55 years old, 56-65 years old or older than 65 years old. In oneaspect, said subject (e.g., in need of treatment) has a disease orcondition chosen from metabolic syndrome, diabetes (e.g., Type 2Diabetes), hypertension, obesity, hypogonadism, hypertriglyceridemia,fatty liver disease, liver fibrosis, steatosis, cirrhosis, hepatitis,cardiovascular disease, NASH, NAFLD, primary sclerosing cholangitis, iswaiting for a liver transplant, has received a liver transplant, primarybiliary cholangitis, a liver disease or condition associated withchronic inflammation, hepatocellular carcinoma, graft versus hostdisease e.g., related to liver transplant, an autoimmune disease relatedto the liver (or has a biomarker level related to or indicative of oneor more of these diseases). In one aspect, said method comprisesidentifying a subject in need of treatment. In a specific aspect, thesubject in need of treatment is treated with one or more additionaltherapeutic agents (e.g., combination therapy). Additionally, thisparagraph is to be read as being specific incorporated into eachspecific method or method embodiment described in the DetailedDescription.

Accordingly, in one embodiment, a method of treating a liver disease orcondition is provided, said method comprising identifying a subject witha biomarker associated with said liver disease or condition where thebiomarker is an imaging biomarker (e.g., liver) or a liver histologybiomarker and orally administering to said subject a pharmaceuticalcomposition comprising a testosterone ester (e.g., testosteroneundecanoate or testosterone tridecanoate) in an amount sufficient toreduce the level of the biomarker or reduce the rate of increase of thebiomarker. In one aspect of this method, the subject has testosteronedeficiency. In one aspect, said subject in need of treatment hastestosterone deficiency with serum testosterone levels of less than 350ng/dL, 300 ng/dL, 250 ng/dL, 200 ng/dL, 150 ng/dL or 100 ng/dL for amale subject or 1/10th of these values for a female subject. In oneaspect, said method comprise oral administration of 200 mg to 750 mg oftestosterone undecanoate per day to a male subject. In one aspect, saidmethod comprise oral administration of 300 mg to 600 mg of testosteroneundecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of 450 mg of testosterone undecanoate perday to a male subject. In one aspect, said method comprises oraladministration of about 400 mg to 2000 mg of testosterone tridecanoateper day to a male subject. In one aspect, said method comprises oraladministration of about 600 mg to 1800 mg of testosterone tridecanoateper day to a male subject. In one aspect, said method comprises oraladministration of about 500 mg, 750 mg, 1000 mg, or 1250 mg oftestosterone tridecanoate per day to a male subject. These dose rangesare typically those for male subjects whereas the female dose rangecorresponds to about 1/10th- 1/15th of these values. In one aspect thesubject is from 18-25 years old, 26-35 years old, 36-45 years old, 45-55years old, 56-65 years old or older than 65 years old. In one aspect,said subject (e.g., in need of treatment) has a disease or conditionchosen from metabolic syndrome, diabetes (e.g., Type 2 Diabetes),hypertension, obesity, hypogonadism, hypertriglyceridemia, fatty liverdisease, liver fibrosis, steatosis, cirrhosis, hepatitis, cardiovasculardisease, NASH, NAFLD, primary sclerosing cholangitis, is waiting for aliver transplant, has received a liver transplant, primary biliarycholangitis, a liver disease or condition associated with chronicinflammation, hepatocellular carcinoma, graft versus host disease e.g.,related to liver transplant, an autoimmune disease related to the liver(or has a biomarker level related to or indicative of one or more ofthese diseases). In one aspect, said method comprises identifying asubject in need of treatment. In one aspect, the disease or condition isa comorbidity of testosterone deficiency. In a specific aspect, thesubject in need of treatment is treated with one or more additionaltherapeutic agents (e.g., combination therapy). Additionally, thisparagraph is to be read as being specifically incorporated into eachspecific method or method embodiment described in the DetailedDescription.

In some aspects of the methods described above and elsewhere in thisdisclosure, male subjects having serum testosterone levels in the rangeof less than 400 ng/dL, less than 450 ng/dL, less than 500 ng/dL, lessthan 550 ng/dL, less than 600 ng/dL, or less than 700 ng/dL can betreated with the compositions described herein in accordance withmethodology described herein.

In some aspects of the methods described above and elsewhere in thisdisclosure, male subjects having serum testosterone levels in the rangeof 50-100 ng/dL, 100-150 ng/dL, 150-200 ng/dL, 200-250 ng/dL, 250-300ng/dL, 300-350 ng/dL, 350-400 ng/dL, 400-450 ng/dL, 450-500 ng/dL,550-600 ng/dL, 600-700 ng/dL, or any combination of these ranges can betreated with the compositions described herein in accordance withmethodology described herein.

In some aspects of the methods described above and elsewhere in thisdisclosure, male subjects having serum SHBG levels in the range of lessthan 20 nmol/L, less than 30 nmol/L, less than 40 nmol/L, less than 50nmol/L, less than 60 nmol/L, less than 70 nmol/L, less than 80 nmol/L,less than 90 nmol/L, less than 100 nmol/L, less than 150 nmol/L, lessthan 200 nmol/L, less than 300 nmol/L, less than 400 nmol/L, or e.g.,less than 1000 ng/dL can be treated with the compositions describedherein in accordance with methodology described herein. These serum SHBGranges can be used in conjunction with the serum testosterone levelsdescribed herein for specific populations particularly suited totreatment as described herein.

In some aspects of the methods described above and elsewhere in thisdisclosure, male subjects having serum testosterone levels in the rangeof 1-20 nmol/L, 20-25 nmol/L, 25-30 nmol/L, 30-35 nmol/L, 35-40 nmol/L,40-45 nmol/L, 45-50 nmol/L, 50-55 nmol/L, 55-60 nmol/L, 60-65 nmol/L,65-80 nmol/L, 80-100 nmol/L, 100-125 nmol/L, 125-150 nmol/L, 150-200nmol/L, 200-300 nmol/L, 300-450 nmol/L, or e.g., 450-750 nmol/L, or anycombination of these ranges can be treated with the compositionsdescribed herein in accordance with methodology described herein. Theseserum SHBG ranges can be used in conjunction with the serum testosteronelevels described herein for specific populations particularly suited totreatment as described herein.

In one aspect of each of the methods described herein (e.g., eachparagraph above in the Summary and each method embodiment of theDetailed Description), the method increases the serum testosterone levelof the subject. In one aspect, the method increases the serumtestosterone level (e.g., C_(ave0-24)) of the subject by at least 10,20, 30, 40, or 50 ng/dL over the subject's baseline (pre-treatment)value (e.g., for a male subject or adjusted accordingly for female orpediatric subjects). In one aspect, the method increases the serumtestosterone level (e.g., C_(ave0-24)) of the subject by at least 30,50, 75, 100, 150, 200, 300, 400 or 500 ng/dL over the subject's baseline(pre-treatment) value (e.g., for a male subject or adjusted accordinglyfor female or pediatric subjects). The baseline serum testosterone levelfor the subject can be determined by a single morning blood draw.Alternatively, the baseline serum testosterone level can be determinedby the average of two morning blood draws from different days. Theincrease over the baseline value can be estimated as a C_(ave) serumtestosterone level in a manner deemed appropriate by a relevant medicalprofessional. For example, the C_(ave) serum testosterone level can beestimated as C_(ave0-24), C_(ave0-12), C_(ave0-8), C_(ave0-6),C_(ave0-4), C_(ave0-3) and C_(ave0-2). Alternatively, a clinician canascertain that a sufficient increase in serum testosterone level hasoccurred via the observation of clinical outcomes or characteristics(e.g., improvement in symptoms), or modulation of one or morebiomarkers.

In another aspect of each of the methods described herein (e.g., eachparagraph above in the Summary and each method embodiment of theDetailed Description), the method produces a serum testosterone profileover a 24-hour period that approximates the pattern of a healthy youngsubject (not necessarily the absolute levels). That is to say there isan increase in serum testosterone levels in the morning which tapers offduring the remainder of the day. Thus, in one aspect the 24-hour serumtestosterone profile is characterized as substantially different thanthat provided by other means of testosterone therapy. For example,commonly used and prescribed testosterone therapies include transdermaltestosterone therapy which over the course of a 24-hour period producesa relative flat pharmacokinetic profile or injectable testosteronetherapies (e.g., intramuscular or subcutaneously) which providerelatively flat pharmacokinetic profiles over a 24-hour period andlonger, depending on the specific therapy. Another way of characterizingthis difference is the difference or delta between serum testosteroneCm. and serum testosterone C_(ave0-24). With both transdermal andinjectable therapy the difference between serum testosterone C_(max) andserum testosterone C_(ave0-24) is relatively small compared to that oforally administered testosterone therapies. Thus, in some aspects, themethods and compositions described herein provide C_(max) to C_(ave)ratios (e.g., C_(max)/C_(ave0-24)) of greater than 1.1, 1.2, 1.3, 1.4,1.5, 1.6, 1.7, 1.8, 1.9 or 2.0. Thus, in some aspects, the methods andcompositions described herein provide C_(max) to C_(ave) ratios (e.g.,C_(max)/C_(ave0-24)) of less than 100, 90, 80, 70, 60, 50, 40, 35, 30 or25. In some aspects, the ratio of C_(max)/C_(ave0-24) is defined as arange defined by any two values in the previous two sentences.

In one embodiment, the methods described above can include the use of aninjectable or transdermal testosterone therapy in conjunction with anoral therapy. For example, the injectable or transdermal therapy canincrease the subject's basal serum testosterone level and the oraltherapy can be used to provide a 24-hour serum testosterone profile thatmimics a normal physiological profile. Alternatively, the methodsdescribed herein can be adapted for use with non-oral testosteronetherapies including but not limited to (1) injectable testosteroneproducts e.g., testosterone enanthate, testosterone propionate,testosterone undecanoate, or another testosterone ester (2) transdermalor topical testosterone products like ANDROGEL, Testim, or Axiron,buccal testosterone products, (3) nasal testosterone products or anyother androgen based therapy (e.g., androgen receptor agonist). In aspecific aspect, these non-oral products can be used to target thespecific disease states, populations, biomarkers and the such asdescribed for the oral compositions.

In one embodiment, the methods described herein involve oraladministration of a testosterone ester (e.g., testosterone undecanoate,testosterone tridecanoate, or a combination thereof) formulated withvitamin E, a vitamin E prodrug, or a vitamin E derivative. In apreferred aspect, the Vitamin E compound is d-alpha-tocopherol ord-alpha tocopherol acetate. In another preferred aspect, the amount ofd-alpha-tocopherol (or it's acetate) administered per day is from about100 IU to about 2000 IU, 200 IU to about 1600 IU per day, about 400 IUto about 1000 IU per day or about 600 IU to 900 IU per day. Theseamounts can be co-formulated with the testosterone esters oradministered separately. The exemplary formulations described herein canbe adapted accordingly to use d-alpha-tocopherol (or e.g., a prodrugthereof (d-alpha-tocopheryl acetate)), tocotrienol and other relatedVitamin E related compounds.

Without wishing to be bound by theory, it is believed the compositionsand method described herein are useful and can be used to treatsteatosis (or fibrosis or symptoms thereof) in any tissue or cell,including, but not limited to, one or more one or more of the following:pancreatic steatosis, renal steatosis, cardiac steatosis, pulmonarysteatosis, intestinal steatosis, cerebral steatosis, and muscularsteatosis, or a symptom thereof. In some aspects, the cell or tissuesexpresses androgen receptor.

Without wishing to be bound by theory, it is believed the compositionsand method described herein are useful and can be used to treatmacrovesicular steatosis or microvesicular steatosis.

Male hypogonadism (testosterone, T, level <300 ng/dL) is anunderappreciated comorbidity in non-alcoholic fatty liver disease(NAFLD)/steatohepatitis (NASH). In addition to the well-established linkbetween low T levels and facets of the metabolic syndrome (obesity,hypertension, hypertriglyceridemia, and type 2 diabetes), hypogonadismis also associated with NAFLD/NASH in males.

This disclosure relates to the prevalence of fatty liver in hypogonadalpatients, as identified by Magnetic Resonance Imaging-Proton Density FatFraction (MRI-PDFF), a non-invasive quantitative biomarker of liver fatcontent.

In a prospective design open-label, multi-center, single arm ‘Liver FatStudy’ evaluating LPCN 1144 (oral testosterone undecanoate) treatment inhypogonadal patients, baseline % liver fat was assessed via MRI-PDFF ina subset of study patients (N=36).

The prevalence of features of the metabolic syndrome in the studypopulation was: 81% obese, 58% hypertriglyceridemia, 28% hypertensive,and 17% type 2 diabetes. Body Mass Index (BMI), T level, and liver fatfraction were 34±6 kg/m2, 199±61 ng/dL, and 8.8±7.9% (mean±SD),respectively. Based on liver fat ≥5%, about 70% of hypogonadal patientswere identified as having NAFLD. Among hypogonadal patients with NAFLD,obesity was the most prevalent comorbidity (88%). Moreover, theprevalence of NAFLD increased in hypogonadal patients with increasingBMI, with the prevalence rising to 100% with Class III obesity (BMI≥40kg/m2).

In conclusion, a high prevalence of NAFLD was observed in this Liver FatStudy. Among the evaluated comorbidities, obesity has the strongestassociation with NAFLD in the hypogonadal male patients. Thus providedherein is a method of treating a subject in need of treatment, saidmethod comprising determining (1) the subject's serum or plasmatestosterone level; (2) the subject's BMI, wherein a subject having (A)low testosterone or is hypogonadal and (B) is obese or has a BMI of 30kg/m2 or greater, is treated for fatty liver disease. In anotherimplementation, a method of diagnosing a subject is provided, saidmethod comprising determining (1) the subject's serum or plasmatestosterone level; (2) the subject's BMI, wherein a subject having (A)low testosterone or is hypogonadal and (B) is obese or has a BMI of 30kg/m2 or greater, is likely to have fatty liver disease and is assessedby a liver imaging technique or has one or more biomarkers assessed todetermine the stage of fatty liver disease. The method can furthercomprise administering to said subject a pharmaceutical agent fortreating NAFLD or NASH.

Thus, also provided herein are methods for diagnosing, staging,prognosing and treating subjects having fatty liver disease.

It is to be understood that the methods described in this section areapplicable to the methods described for the specific conditions/diseasesin the Detailed Description.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a summary of an analysis of liver function enzyme changesfrom baseline to end of study values comparing obese (e.g., BMI>30kg/m²) to non-obese subjects in the study of Example 1.

FIG. 2 shows a summary of an analysis of serum alanine transaminaselevels of subjects in the study of Example 1, comparing baseline valuesto end of study values. In this figure and the remaining figures, Q-maxrefers to the maximum value of the biomarker for the specified quartile.For example, in this figure the first quartile are those subjects havingserum alanine transaminase levels of less than or equal to 21 U/L, thesecond quartile are those subjects having serum alanine transaminaselevels between 21 U/L and less than or equal to 27 U/L.

FIG. 3 shows a summary of an analysis of serum alanine transaminaselevels of subjects in the highest quartile of alanine transaminaselevels at baseline during the course of the study of Example 1.

FIG. 4 shows a summary of an analysis of serum aspartate transaminaselevels of subjects comparing baseline to end of study values in thestudy of Example 1.

FIG. 5 shows a summary of an analysis of serum alkaline phosphataselevels of subjects comparing baseline to end of study values in thestudy of Example 1.

FIG. 6 shows a summary of analyses of serum alkaline phosphatase levelsof subjects comparing baseline to end of study values in the studies ofExamples 1, 2, 3, and 4.

FIG. 7 shows a summary of an analysis of serum gamma-glutamyltransferase levels of subjects comparing baseline to end of study valuesin the study of Example 1.

FIG. 8 shows a summary of an analysis of serum bilirubin levels ofsubjects comparing baseline to end of study values in the study ofExample 1.

FIG. 9 shows a summary of an analysis of serum triglyceride levels ofdiabetic and non-diabetic subjects at baseline compared to end of studyvalues in the study of Example 1.

FIG. 10 shows a summary of an analysis of serum triglyceride levels ofsubjects having lipid metabolism disorder and non-lipid metabolismdisorder subjects at baseline compared to end of study values in thestudy of Example 1.

FIG. 11 shows a summary of an analysis of serum triglyceride levels ofsubjects at baseline compared to end of study in the study of Example 1.

FIG. 12 shows a summary of an analysis of serum triglyceride levels ofsubjects at baseline compared to end of study in the study of Examples1, 2, and 4.

FIG. 13 shows a summary of an analysis of serum LDL levels of subjectsat baseline compared to end of study in the study of Example 1.

FIG. 14 shows a summary of an analysis of serum total cholesterol levelsof subjects at baseline compared to end of study in the study of Example1.

FIG. 15 shows a summary of an analysis of serum non-HDL cholesterollevels of subjects at baseline compared to end of study in the study ofExample 1.

FIG. 16 illustrates the difference in serum testosterone levels for oraltestosterone therapy (results from Example 2) and transdermal therapy(which is also similar to injectable therapies in the sense of arelatively flat profile).

FIG. 17 shows the prevalence of comorbidities in the male hypogonadalpopulation studied herein.

FIG. 18 shows the mean liver fat % as a function of BMI classes in themale hypogonadal population studied herein.

FIG. 19 shows percent of subjects having NAFLD as defined by liver fatcut-off values of 5% and 8%, as a function of BMI class, for malehypogonadal population studied herein.

FIG. 20 the distribution of liver fat % values across the malehypogonadal population studied herein.

FIG. 21 shows the prevalence of comorbidities in the male hypogonadalpopulation studied herein according to liver fat % cut-offs.

The Figures illustrate specific aspects of the compositions and methodsfor using such compositions. Together with the following description,the Figures demonstrate and explain the principles of the methods andcompositions produced through these methods. In the drawings, thethickness of layers and regions are exaggerated for clarity. Also,directions (e.g., above, below, top, bottom, side, up, down, under,over, upper, lower, horizontal, vertical, “x,” “y,” “z,” etc.), ifprovided, are relative and provided solely by way of example and forease of illustration and discussion and not by way of limitation. Inaddition, where reference is made to a list of elements (e.g., elementsa, b, c), such reference is intended to include any one of the listedelements by itself, any combination of less than all of the listedelements, and/or a combination of all of the listed elements.

DETAILED DESCRIPTION

It was unexpectedly found that androgen receptor modulators e.g.,agonists are useful for improving liver function, liver diseases orconditions and related comorbidities. While a number of modalities fortreating liver disease are described herein in the context of oralandrogen therapy e.g., oral administration of testosterone esters liketestosterone undecanoate, the skilled artisan recognizes in view of thisdisclosure, other androgen receptor agonist can be adapted and employedin these methods such as transdermal, nasal, buccal, and injectabletestosterone products. In addition to testosterone, testosterone estersand the such, other androgen receptor agonists (including selectiveandrogen receptor modulators, anabolic steroids wtc.) may be employedherein as well as methods and compounds, pharmaceuticals, nutritional orvitamin supplements that increase serum testosterone levels, serum freetestosterone levels, or androgen receptor signaling in target tissues orcompartments.

The following description supplies specific details in order to providea thorough understanding of the methods and compositions of theinvention. Nevertheless, the skilled artisan would understand that thecompositions and associated methods of making and using suchcompositions can be implemented and used without employing thesespecific details. Indeed, the compositions and associated methods can beplaced into practice by modifying the illustrated devices and methodsand can be used in conjunction with any other agents and techniquesconventionally used in the industry. For example, while the descriptionrefers to specific indications, it could be modified to be used in otherindications.

It was surprisingly discovered that oral androgen therapy e.g., oraladministration of a pharmaceutical compositions containing atestosterone ester (e.g., or an androgen receptor agonist or anabolicagent), is particularly useful for treating liver disease, comorbiditiesof testosterone deficiency, and can reduce mortality, and ameliorate orimprove biomarkers related to these conditions or diseases. For example,it was found that the instant methods and compositions reduce relevantbiomarker levels in patients having elevated biomarkers related to liverdisease (e.g., fatty liver disease, liver fibrosis, alcoholic liverdisease, hepatitis, steatosis, NAFLD, NASH, NASH with cirrhosis, andcomorbidities of testosterone deficiency). Unexpectedly, as describedherein, the reduction in serum alkaline phosphatase levels wassignificantly better with oral therapy than that observed with once aday topical testosterone product (e.g, ANDROGEL)™, a marketedtestosterone replacement therapy administered via the transdermal route.Other unexpected findings include substantial reductions (orimprovements) in triglyceride levels, biomarkers of liver injury, andbiomarkers for other diseases and conditions associated withlipoprotein-associated phospholipase A2, a biomarker of cardiovasculardisease. Thus, in one implementation, the methods described hereinincrease the ratio of serum testosterone levels to alkaline phosphatase.Thus, in one implementation, the methods described herein increase theratio of serum testosterone levels to serum triglycerides.

While not wishing to be bound by theory, it is believed in some aspectsdescribed herein, that the methods and compositions present a therapyapproximating a normal physiological pattern of serum testosteronelevels with peaks and troughs of serum testosterone levels as opposed tothe relative flat profile of other testosterone therapies liketransdermal products and injectable products. It is believed that, insome aspects, the more normal physiological pattern of serumtestosterone levels provides less suppression of endogenous serumtestosterone levels and relative hormones/biomarkers leading to theunexpected results described herein.

Concentrations, amounts, levels and other numerical data may beexpressed or presented herein in a range format. It is to be understoodthat such a range format is used merely for convenience and brevity andthus should be interpreted flexibly to include not only the numericalvalues explicitly recited as the limits of the range, but also toinclude all the individual numerical values or sub-ranges or decimalunits encompassed within that range as if each numerical value andsub-range is explicitly recited. As an illustration, a numerical rangeof “about 1 to about 5” should be interpreted to include not only theexplicitly recited values of about 1 to about 5, but also includeindividual values and sub-ranges within the indicated range. Thus,included in this numerical range are individual values such as 2, 3, and4 and sub-ranges such as from 1-3, from 2-4, and from 3-5, etc., as wellas 1, 2, 3, 4, and 5, individually. This same principle applies toranges reciting only one numerical value as a minimum or a maximum.Furthermore, such an interpretation should apply regardless of thebreadth of the range or the characteristics being described.

The terms “serum testosterone” or “serum(17-β)-Hydroxy-4-Androsten-3-one levels,” “serum T levels,” “serumtestosterone concentration,” “plasma testosterone concentration,”“testosterone concentration in the blood,” and “serum testosteroneconcentration,” are used interchangeably and refer to the “total”testosterone concentration which is the sum of the bioavailabletestosterone including free and bound testosterone concentrations.Unless otherwise specified, these values are “observed” testosteroneconcentrations without adjusting or correcting for the base-line serumtestosterone levels in the subject(s). As with any bio-analyticalmeasure, for increased consistency, the method employed to measureinitial serum testosterone levels should be consistent with the methodused to monitor and re-measure serum testosterone levels during clinicaltesting and testosterone therapy for a subject. Unless otherwise stated,“testosterone concentration” refers to serum total testosteroneconcentration.

Average serum testosterone concentrations can be determined usingmethods and practices known in the art. For example, the averagebaseline plasma testosterone concentration of a human male is thearithmetic mean of the total plasma testosterone concentrationdetermined on at least two consecutive time points that are reasonablyspaced from each other, for example from about 1 hour to about 168 hoursapart. In a particular case, the plasma testosterone concentration canbe determined on at least two consecutive times that are about 12 hoursto about 48 hours apart. In another particular method, the plasmatestosterone concentration of the human male can be determined at a timebetween about 5 o'clock and about 11 o'clock in the morning. Further,the plasma testosterone concentration can be the determined by standardanalytical procedures and methods available in the art, such as forexample, automated or manual immunoassay methods, liquid chromatographyor liquid chromatography-tandem mass spectrometry (LC-MSMS) etc.

As used herein, “free testosterone serum concentration”, refers to thetestosterone concentration not bound to protein e.g., SHBG or albumin.In some aspects of the methods described herein, free testosterone serumconcentrations are used instead of serum total testosteroneconcentrations. For example, a subject can appear to have total serumtestosterone levels in the normal range but can be still consideredhypogonadal or testosterone deficient based on free testosterone levels.

As used herein, “in need of treatment” refers to a subject that has adisease or is suspected of having the disease according to variousdiagnostic criteria typically used in practice, or desires treatment oris indicated for treatment. Thus, “in need of treatment” can include thestep of identifying a subject in need of treatment.

As used herein, “identifying a subject in need of treatment” can includethe step of obtaining a biological sample from the subject anddetermining the level of one or more biomarkers as described herein,assessing the histology of a biological sample obtained from saidsubject, performing an imaging analysis on the subject, assessing one ormore clinical characteristics of said subject (e.g., assessing symptomsor overt symptoms), or a combination thereof.

As used herein, the term AUC_(t1-t2) is the area under the curve of aplasma-versus-time graph determined for the analyte from the time “t1 totime t2”. Wherein t1 and t2 are times (in hours) post dosing. ForExample, t1 could be 1 hour and t2 could be 2 hours.

As used herein, the term “C_(avg),” “C_(ave),” or “C-average” are usedinterchangeably, and is determined as the AUC_(t1-t2) mean AUC dividedby the time period (|t1−t2|). For example, C_(avg t0-t8) is the averageplasma concentration over a period of 8 hours from t1=0 to t2=8 hours)post-dosing determined by dividing the AUC tom value by 8. Similarly,C_(avg t0-t2) is the average plasma concentration over a period of 12hours post-dosing determined by dividing the AUC_(t0-t12) value by 12(t1=0-t2=12). Similarly, C_(avg t12-t24) is the average plasmaconcentration over a period of 12 hours post-dosing determined bydividing the AUC_(t12-t24) value by 12 (t1=12-t2=24); C_(avg-t24) is theaverage plasma concentration over a period of 24 hours post-dosingdetermined by dividing the AUC_(t0-t24) value by 24 (t1=0-t2=24), and soon. Unless otherwise stated, all C_(avg) values are considered to beC_(avg-t24) and unless otherwise stated, all the time values areexpressed in hours (h). For example, the term C_(avg t0-t24) denotesC_(avg) from time zero (0) to 24 hours post dosing.

“Androgen receptor agonists” as used herein refers to compounds ormolecules such as testosterone that bind and activate the androgenreceptor. Androgen receptor agonists include, but are not limited to,dihydrotestosterone, mibolerone, testosterone, methyltrienolone,oxandrolone, nandrolone and fluoxymesterone. Where appropriate, fattyacid esters of these androgen receptor agonists can be used hereinaccordingly.

“Testosterone ester” as used herein refers to testosterone esterifiedwith a fatty acid and includes but is not limited to, testosteroneundecanoate, testosterone tridecanoate, testosterone enanthate,testosterone decanoate, testosterone palmitate, testosterone cypionate,and testosterone propionate. In one aspect, a preferred testosteroneester for oral administration according to the methods and compositionsdescribed herein is testosterone undecanoate. In one aspect, a preferredtestosterone ester for oral administration according to the methods andcompositions described herein is testosterone decanoate. In one aspect,a preferred testosterone ester for oral administration according to themethods and compositions described herein is testosterone dodecanoate.In one aspect, a preferred testosterone ester for oral administrationaccording to the methods and compositions described herein istestosterone tridecanoate. In one aspect, a preferred testosterone esterfor oral administration according to the methods and compositionsdescribed herein is testosterone tetradecanoate.

“Fibrosis,” or “Liver Fibrosis” as used herein, refers to theaccumulation of extracellular matrix constituents that occurs followingtrauma, inflammation, tissue repair, immunological reactions, cellularhyperplasia, and neoplasia.

“Normal Range” as used herein refers to a range of values generallyconsidered to be representative of a healthy individual or population.It is understood that “normal range” is general specific to a type ofassay or lab. For example, for a particular analyte, a normal range forone assay or lab can differ as compared to a normal range for anotherassay or lab for the same analyte. Thus, the normal ranges describedherein may vary from lab to lab or assay to assay. The skilled artisanunderstands that the normal ranges disclosed herein can vary fromindividual to individual. The skilled artisan understands that thenormal ranges described herein are typically appropriate for theindicated sample e.g., serum and that other samples e.g., saliva canhave different normal ranges.

“Upper Normal Range” as used herein refers to above the 50% level forthat range. For example, a biomarker may have a normal range of 10-40U/L, according to this definition, the upper normal range is above 25U/L and below 40 U/L. In another example, consider a biomarker having arange of 43-115 U/L, the high normal range is above 79 U/L and below 115U/L.

As used herein, “ALT normal range” refers to the range of serum alaninetransaminase values considered normal for healthy individuals and isfrom about 10-40 U/L according to the assay/lab used in Example 1.

As used herein, “AST normal range” refers to the range of serumaspartate transaminase values considered normal for healthy individualsand is from about 10-43 U/L according to the assay/lab used in Example1.

As used herein, “ALP normal range” refers to the range of serum alkalinephosphatase values considered normal for healthy individuals and is fromabout 43-115 U/L according to the assay/lab used in Example 1.

As used herein, “GGT normal range” refers to the range of serumgamma-glutamyl transferase values considered normal for healthyindividuals and is from about 10-49 U/L according to the assay/lab usedin Example 1.

As used herein, “triglyceride normal range” refers to the range of serumtriglyceride values considered normal for healthy individuals and isfrom about 45-200 mg/dL according to the assay/lab used in Example 1.

As used herein, “LDL normal range” and is from about 50-160 mg/dLaccording to the assay/lab used in Example 1.

As used herein, “desirable total cholesterol” or “total cholesterolnormal range” and for adults is from about 125-200 mg/dL according tothe assay/lab used in Example 1.

As used herein, “non-HDL cholesterol normal range” for adults is 130-159mg/dL (3.4-4.0 mmol/L) is considered near ideal. The skilled artisanrealizes that an ideal level depends on a number of factors and thenormal range is variable depending on these factors.

As used herein, “VLDL” refers to very low density lipoprotein and has anormal range of 2 to 30 mg/dL.

As used herein, “SHBG” refers to sex hormone binding globulin and has anormal range of about 20 to 60 nmol/L for healthy adult males. As withany other of the biomarkers disclosed herein the normal ranges depend ona number of factors including sex and age e.g., Adult female,premenopausal 40-120 nmol/L; Adult female, postmenopausal 28-112 nmol/L;Adult male; 20-60 nmol/L; Infant (1-23 months) 60-252 nmol/L;Prepubertal (2 years-8 years) 72-220 nmol/L; Pubertal female 36-125nmol/L; and Pubertal male 16-100 nmol/L.

As used herein, terms such as fatty liver disease, liver fibrosis,alcoholic liver disease, hepatitis, steatosis, NAFLD, NASH, and NASHwith cirrhosis are given their customary meaning to one of ordinaryskill in the art and such condition are identifiable and diagnosable bymedical professionals such as physicians, hepatologists,gastroenterologists and the like based on assessment of the relevantdisease characteristics in patients.

Methods

As described below, it was discovered that compositions containingsteroids e.g., steroid esters can be used to treat subjects e.g., maleor female human subjects with a variety of diseases and conditionsincluding, but not limited to, those described in the summary sectionherein or as described below. The ordinary skilled artisan understandthat these composition and methods can be used for other diseases andconditions based on this disclosure.

Although some of the description focuses on the oral administration oftestosterone esters, the methods and compositions described herein canbe adapted to other pharmaceuticals such as androgen agonists,androgens, androgenic-anabolic compounds, selective androgen receptormodulators and other compounds that target androgen receptor signalingpathways in view of the studies described herein.

In one embodiment, a method of reducing the risk of steatosisprogressing to cirrhosis in a subject is provided said method comprisingoral administration of a pharmaceutical composition having atestosterone ester (e.g., testosterone undecanoate or testosteronetridecanoate) to said subject. In one aspect, the subject is in need oftreatment e.g., having steatosis or at risk for having steatosisprogressing to cirrhosis. In one aspect, the subject in need oftreatment has one or more biomarkers (or clinical characteristics)indicating an increased risk of steatosis progressing to cirrhosis. Inone aspect, the one or more biomarkers are outside the normal range. Inone aspect, the one or more biomarkers are above the normal range butbelow 2 times the upper limit of the normal range. In one aspect of thismethod, the subject has testosterone deficiency. In one aspect, saidsubject in need of treatment has testosterone deficiency with serumtestosterone levels of less than 350 ng/dL, 300 ng/dL, 250 ng/dL, 200ng/dL, 150 ng/dL or 100 ng/dL. In one aspect, the one or more biomarkersare above the normal range but between 2-3 times the upper limit of thenormal range or more. In one aspect, the one or more biomarkers areabove the normal range but below 2 times the upper limit of the normalrange. In one aspect of this method, the subject has testosteronedeficiency. In one aspect of this method, oral administration of thetestosterone ester reduces the risk of steatosis progressing tocirrhosis while not substantially increasing serum levels of ordecreases serum levels of lipoprotein-associated phospholipase A2. Inone aspect of this method, the subject has alcoholic or non-alcoholicsteatosis. In one aspect of this embodiment, the subject has one or moreof the following comorbidities: obesity, type 2 diabetes, dyslipidemia,cardiovascular disease, thyroid dysfunction, chronic kidney disease,liver disease, osteoporosis, hypogonadism, hypertension, sarcopenia, orcachexia. In one aspect, said method increases said subject's serumtestosterone levels over their baseline. In another aspect, said methodincreases said subject's serum testosterone levels into the normalrange. In one aspect, said method comprises oral administration of 200mg to 750 mg of testosterone undecanoate per day to a male subject. Inone aspect, said method comprise oral administration of 300 mg to 600 mgof testosterone undecanoate per day to a male subject. In one aspect,said method comprises oral administration of 450 mg of testosteroneundecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of about 400 mg to 2000 mg of testosteronetridecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of about 600 mg to 1800 mg of testosteronetridecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of about 500 mg, 750 mg, 1000 mg, or 1250mg of testosterone tridecanoate per day to a male subject. These doseranges are typically those for male subjects whereas the female doserange corresponds to about 1/10^(th)- 1/15^(th) of these values. In oneaspect the subject is from 18-25 years old, 26-35 years old, 36-45 yearsold, 45-55 years old, 56-65 years old or older than 65 years old. In oneaspect, the biomarker is one or more chosen from ALP, ALT, AST, GGT,triglycerides, LDL, cholesterol, liver biopsy, inflammation biomarkers,non-HDL cholesterol, hematocrit, hemoglobin, lipoprotein phospholipaseA2, bilirubin, albumin, SHBG, any specific biomarkers disclosed in theTables of Example 1, imaging biomarkers, liver histology biomarkers,biomarkers in the literature related to the disease and conditiondescribed herein, and liver damage biomarkers. In one aspect of thisembodiment, the subject has one or more of the following comorbidities:obesity, type 2 diabetes, dyslipidemia, cardiovascular disease, thyroiddysfunction, chronic kidney disease, liver disease, osteoporosis,hypogonadism, hypertension, sarcopenia, or cachexia.

In another embodiment, a method of increasing the amount of time asubject having cirrhosis can survive while waiting for a livertransplant is provided said method comprising oral administration of apharmaceutical composition having a testosterone ester (e.g.,testosterone undecanoate or testosterone tridecanoate) to said subject.In one aspect, the subject is in need of treatment e.g., havingcirrhosis or at risk of dying from cirrhosis or is waiting for a livertransplant. In one aspect, the subject in need of treatment has one ormore biomarkers (or clinical characteristics) indicating compromisedsurvival time while waiting for a liver transplant. In one aspect, theone or more biomarkers are outside the normal range. In one aspect, theone or more biomarkers are above the normal range but below 2 times theupper limit of the normal range. In one aspect of this method, thesubject has testosterone deficiency. In one aspect, the one or morebiomarkers are above the normal range but between 2-3 times the upperlimit of the normal range or more. In one aspect, the one or morebiomarkers are above the normal range but below 2 times the upper limitof the normal range. In one aspect of this method, the subject hastestosterone deficiency. In one aspect, said subject in need oftreatment has testosterone deficiency with serum testosterone levels ofless than 350 ng/dL, 300 ng/dL, 250 ng/dL, 200 ng/dL, 150 ng/dL or 100ng/dL. In one aspect of this method, oral administration of thetestosterone ester increases the amount of time a subject havingcirrhosis can survive while waiting for a liver transplant while notsubstantially increasing serum levels of or decreases serum levels oflipoprotein-associated phospholipase A2. In one aspect, the treatmentreduces the subject's MELD score or reduces the rate of increase. In oneaspect, said method increases said subject's serum testosterone levelsover their baseline. In another aspect, said method increases saidsubject's serum testosterone levels into the normal range. In oneaspect, said method comprises oral administration of 200 mg to 750 mg oftestosterone undecanoate per day to a male subject. In one aspect, saidmethod comprises oral administration of 300 mg to 600 mg of testosteroneundecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of 450 mg of testosterone undecanoate perday to a male subject. In one aspect, said method comprises oraladministration of about 400 mg to 2000 mg of testosterone tridecanoateper day to a male subject. In one aspect, said method comprises oraladministration of about 600 mg to 1800 mg of testosterone tridecanoateper day to a male subject. In one aspect, said method comprises oraladministration of about 500 mg, 750 mg, 1000 mg, or 1250 mg oftestosterone tridecanoate per day to a male subject. These dose rangesare typically those for male subjects whereas the female dose rangecorresponds to about 1/10^(th)- 1/15^(th) of these values. In one aspectthe subject is from 18-25 years old, 26-35 years old, 36-45 years old,45-55 years old, 56-65 years old or older than 65 years old. In oneaspect, the biomarker is one or more chosen from ALP, ALT, AST, GGT,triglycerides, LDL, cholesterol, liver biopsy, inflammation biomarkers,non-HDL cholesterol, hematocrit, hemoglobin, lipoprotein phospholipaseA2, bilirubin, albumin, SHBG, any specific biomarkers disclosed in theTables of Example 1, imaging biomarkers, liver histology biomarkers,biomarkers in the literature related to the disease and conditiondescribed herein, and liver damage biomarkers. In one aspect of thisembodiment, the subject has one or more of the following comorbidities:obesity, type 2 diabetes, dyslipidemia, cardiovascular disease, thyroiddysfunction, chronic kidney disease, liver disease, osteoporosis,hypogonadism, hypertension, sarcopenia, or cachexia.

In yet another embodiment, a method of reducing fatty liver in a subjectis provided said method comprising oral administration of apharmaceutical composition having a testosterone ester (e.g.,testosterone undecanoate or testosterone tridecanoate) to said subject.In one aspect, the subject is in need of treatment e.g., has fatty liveror fatty liver disease or has increased risk of having fatty liverdisease. In one aspect, the subject in need of treatment has one or morebiomarkers (or clinical characteristics) indicating fatty liver orincreasing fatty liver. In one aspect, the one or more biomarkers areoutside the normal range. In one aspect, the one or more biomarkers areabove the normal range but below 2 times the upper limit of the normalrange. In one aspect of this method, the subject has testosteronedeficiency. In one aspect, said subject in need of treatment hastestosterone deficiency with serum testosterone levels of less than 350ng/dL, 300 ng/dL, 250 ng/dL, 200 ng/dL, 150 ng/dL or 100 ng/dL. In oneaspect, the one or more biomarkers are above the normal range butbetween 2-3 times the upper limit of the normal range or more. In oneaspect, the one or more biomarkers are above the normal range but below2 times the upper limit of the normal range. In one aspect of thismethod, the subject has testosterone deficiency. In one aspect of thismethod, the subject has testosterone deficiency. In one aspect of thismethod, oral administration of the testosterone ester reduces fattyliver while not substantially increasing serum levels of or decreasesserum levels of lipoprotein-associated phospholipase A2. In one aspect,said method increases said subject's serum testosterone levels overtheir baseline. In another aspect said method increases said subject'sserum testosterone levels into the normal range. In one aspect, saidmethod comprises oral administration of 200 mg to 750 mg of testosteroneundecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of 300 mg to 600 mg of testosteroneundecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of 450 mg of testosterone undecanoate perday to a male subject. In one aspect, said method comprises oraladministration of about 400 mg to 2000 mg of testosterone tridecanoateper day to a male subject. In one aspect, said method comprises oraladministration of about 600 mg to 1800 mg of testosterone tridecanoateper day to a male subject. In one aspect, said method comprises oraladministration of about 500 mg, 750 mg, 1000 mg, or 1250 mg oftestosterone tridecanoate per day to a male subject. These dose rangesare typically those for male subjects whereas the female dose rangecorresponds to about 1/10^(th)- 1/15^(th) of these values. In one aspectthe subject is from 18-25 years old, 26-35 years old, 36-45 years old,45-55 years old, 56-65 years old or older than 65 years old. In oneaspect, the biomarker is one or more chosen from ALP, ALT, AST, GGT,triglycerides, LDL, cholesterol, liver biopsy, inflammation biomarkers,non-HDL cholesterol, hematocrit, hemoglobin, lipoprotein phospholipaseA2, bilirubin, albumin, SHBG, any specific biomarkers disclosed in theTables of Example 1, imaging biomarkers, liver histology biomarkers,biomarkers in the literature related to the disease and conditiondescribed herein, and liver damage biomarkers. In one aspect of thisembodiment, the subject has one or more of the following comorbidities:obesity, type 2 diabetes, dyslipidemia, cardiovascular disease, thyroiddysfunction, chronic kidney disease, liver disease, osteoporosis,hypogonadism, hypertension, sarcopenia, or cachexia.

In yet another embodiment, a method of reducing the rate of fatty liverincrease in a subject is provided said method comprising oraladministration of a pharmaceutical composition having a testosteroneester (e.g., testosterone undecanoate or testosterone tridecanoate) tosaid subject. In one aspect, the subject is in need of treatment e.g.,has fatty liver or increasing fatty liver. In one aspect, the subject inneed of treatment has one or more biomarkers (or clinicalcharacteristics) indicating increasing fatty liver. In one aspect, theone or more biomarkers are outside the normal range. In one aspect, theone or more biomarkers are above the normal range but below 2 times theupper limit of the normal range. In one aspect of this method, thesubject has testosterone deficiency. In one aspect, said subject in needof treatment has testosterone deficiency with serum testosterone levelsof less than 350 ng/dL, 300 ng/dL, 250 ng/dL, 200 ng/dL, 150 ng/dL or100 ng/dL. In one aspect, the one or more biomarkers are above thenormal range but between 2-3 times the upper limit of the normal rangeor more. In one aspect, the one or more biomarkers are above the normalrange but below 2 times the upper limit of the normal range. In oneaspect of this method, oral administration of the testosterone esterreduces the rate of fatty liver increase while not substantiallyincreasing serum levels of or decreases serum levels oflipoprotein-associated phospholipase A2. In one aspect, said methodincreases said subject's serum testosterone levels over their baseline.In another aspect said method increases said subject's serumtestosterone levels into the normal range. In one aspect, said methodcomprises oral administration of 200 mg to 750 mg of testosteroneundecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of 300 mg to 600 mg of testosteroneundecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of 450 mg of testosterone undecanoate perday to a male subject. In one aspect, said method comprises oraladministration of about 400 mg to 2000 mg of testosterone tridecanoateper day to a male subject. In one aspect, said method comprises oraladministration of about 600 mg to 1800 mg of testosterone tridecanoateper day to a male subject. In one aspect, said method comprises oraladministration of about 500 mg, 750 mg, 1000 mg, or 1250 mg oftestosterone tridecanoate per day to a male subject. These dose rangesare typically those for male subjects whereas the female dose rangecorresponds to about 1/10^(th)- 1/15^(th) of these values. In one aspectthe subject is from 18-25 years old, 26-35 years old, 36-45 years old,45-55 years old, 56-65 years old or older than 65 years old. In oneaspect, the biomarker is one or more chosen from ALP, ALT, AST, GGT,triglycerides, LDL, cholesterol, liver biopsy, inflammation biomarkers,non-HDL cholesterol, hematocrit, hemoglobin, lipoprotein phospholipaseA2, bilirubin, albumin, SHBG, any specific biomarkers disclosed in theTables of Example 1, imaging biomarkers, liver histology biomarkers,biomarkers in the literature related to the disease and conditiondescribed herein, and liver damage biomarkers. In one aspect of thisembodiment, the subject has one or more of the following comorbidities:obesity, type 2 diabetes, dyslipidemia, cardiovascular disease, thyroiddysfunction, chronic kidney disease, liver disease, osteoporosis,hypogonadism, hypertension, sarcopenia, or cachexia.

In one embodiment, a method of reducing progression or the risk ofprogression of fatty liver to NAFLD in a subject having or suspected ofhaving fatty liver is provided said method comprising oraladministration of a pharmaceutical composition having a testosteroneester (e.g., testosterone undecanoate or testosterone tridecanoate) tosaid subject. In one aspect, the subject is in need of treatment e.g.,has fatty liver or is at risk of having fatty liver progressing toNAFLD. In one aspect, the subject in need of treatment has one or morebiomarkers (or clinical characteristics) indicating an increased risk offatty liver progressing to NAFLD. In one aspect, the one or morebiomarkers are outside the normal range. In one aspect, the one or morebiomarkers are above the normal range but below 2 times the upper limitof the normal range. In one aspect of this method, the subject hastestosterone deficiency. In one aspect, the one or more biomarkers areabove the normal range but between 2-3 times the upper limit of thenormal range or more. In one aspect, the one or more biomarkers areabove the normal range but below 2 times the upper limit of the normalrange. In one aspect of this method, the subject has testosteronedeficiency. In one aspect, said subject in need of treatment hastestosterone deficiency with serum testosterone levels of less than 350ng/dL, 300 ng/dL, 250 ng/dL, 200 ng/dL, 150 ng/dL or 100 ng/dL. In oneaspect of this method, oral administration of the testosterone esterreduces progression of fatty liver disease to NAFLD while notsubstantially increasing serum levels of or decreases serum levels oflipoprotein-associated phospholipase A2. In one aspect, said methodincreases said subject's serum testosterone levels over their baseline.In another aspect said method increases said subject's serumtestosterone levels into the normal range. In one aspect, said methodcomprise oral administration of 200 mg to 750 mg of testosteroneundecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of 300 mg to 600 mg of testosteroneundecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of 450 mg of testosterone undecanoate perday to a male subject. In one aspect, said method comprises oraladministration of about 400 mg to 2000 mg of testosterone tridecanoateper day to a male subject. In one aspect, said method comprises oraladministration of about 600 mg to 1800 mg of testosterone tridecanoateper day to a male subject. In one aspect, said method comprises oraladministration of about 500 mg, 750 mg, 1000 mg, or 1250 mg oftestosterone tridecanoate per day to a male subject. These dose rangesare typically those for male subjects whereas the female dose rangecorresponds to about 1/10^(th)- 1/15^(th) of these values. In one aspectthe subject is from 18-25 years old, 26-35 years old, 36-45 years old,45-55 years old, 56-65 years old or older than 65 years old. In oneaspect, the biomarker is one or more chosen from ALP, ALT, AST, GGT,triglycerides, LDL, cholesterol, liver biopsy, inflammation biomarkers,non-HDL cholesterol, hematocrit, hemoglobin, lipoprotein phospholipaseA2, bilirubin, albumin, SHBG, any specific biomarkers disclosed in theTables of Example 1, imaging biomarkers, liver histology biomarkers,biomarkers in the literature related to the disease and conditiondescribed herein, and liver damage biomarkers. In one aspect of thisembodiment, the subject has one or more of the following comorbidities:obesity, type 2 diabetes, dyslipidemia, cardiovascular disease, thyroiddysfunction, chronic kidney disease, liver disease, osteoporosis,hypogonadism, hypertension, sarcopenia, or cachexia.

In yet another embodiment, a method of reducing progression or the riskof progression of NAFLD to NASH in a subject having or suspected ofhaving NAFLD is provided said method comprising oral administration of apharmaceutical composition having a testosterone ester (e.g.,testosterone undecanoate or testosterone tridecanoate) to said subject.In one aspect, the subject is in need of treatment e.g., has NAFLD or isat risk of having NAFLD progressing to NASH. In one aspect, the subjectin need of treatment has one or more biomarkers (or clinicalcharacteristics) indicating an increased risk of NAFLD progressing toNASH. In one aspect, the one or more biomarkers are outside the normalrange. In one aspect, the one or more biomarkers are above the normalrange but below 2 times the upper limit of the normal range. In oneaspect of this method, the subject has testosterone deficiency. In oneaspect, the one or more biomarkers are above the normal range butbetween 2-3 times the upper limit of the normal range or more. In oneaspect, the one or more biomarkers are above the normal range but below2 times the upper limit of the normal range. In one aspect of thismethod, the subject has testosterone deficiency. In one aspect, saidsubject in need of treatment has testosterone deficiency with serumtestosterone levels of less than 350 ng/dL, 300 ng/dL, 250 ng/dL, 200ng/dL, 150 ng/dL or 100 ng/dL. In one aspect of this method, oraladministration of the testosterone ester reduces the risk of steatosisprogressing to cirrhosis while not substantially increasing serum levelsof or decreases serum levels of lipoprotein-associated phospholipase A2.In one aspect of this method, oral administration of the testosteroneester reduces the risk of NAFLD progressing to NASH while notsubstantially increasing serum levels of or decreases serum levels oflipoprotein-associated phospholipase A2. In one aspect, said methodincreases said subject's serum testosterone levels over their baseline.In another aspect said method increases said subject's serumtestosterone levels into the normal range. In one aspect, said methodcomprises oral administration of 200 mg to 750 mg of testosteroneundecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of 300 mg to 600 mg of testosteroneundecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of 450 mg of testosterone undecanoate perday to a male subject. In one aspect, said method comprises oraladministration of about 400 mg to 2000 mg of testosterone tridecanoateper day to a male subject. In one aspect, said method comprises oraladministration of about 600 mg to 1800 mg of testosterone tridecanoateper day to a male subject. In one aspect, said method comprises oraladministration of about 500 mg, 750 mg, 1000 mg, or 1250 mg oftestosterone tridecanoate per day to a male subject. These dose rangesare typically those for male subjects whereas the female dose rangecorresponds to about 1/10^(th)- 1/15^(th) of these values. In one aspectthe subject is from 18-25 years old, 26-35 years old, 36-45 years old,45-55 years old, 56-65 years old or older than 65 years old. In oneaspect, the biomarker is one or more chosen from ALP, ALT, AST, GGT,triglycerides, LDL, cholesterol, liver biopsy, inflammation biomarkers,non-HDL cholesterol, hematocrit, hemoglobin, lipoprotein phospholipaseA2, bilirubin, albumin, SHBG, any specific biomarkers disclosed in theTables of Example 1, imaging biomarkers, liver histology biomarkers,biomarkers in the literature related to the disease and conditiondescribed herein, and liver damage biomarkers. In one aspect of thisembodiment, the subject has one or more of the following comorbidities:obesity, type 2 diabetes, dyslipidemia, cardiovascular disease, thyroiddysfunction, chronic kidney disease, liver disease, osteoporosis,hypogonadism, hypertension, sarcopenia, or cachexia.

In one embodiment, a method of reducing progression or the risk ofprogression of NASH to cirrhosis in a subject having or suspected ofhaving NASH is provided said method comprising oral administration of apharmaceutical composition having a testosterone ester (e.g.,testosterone undecanoate or testosterone tridecanoate) to said subject.In one aspect, the subject is in need of treatment e.g., has NASH or isat risk of having NASH progressing to cirrhosis. In one aspect, thesubject in need of treatment has one or more biomarkers (or clinicalcharacteristics) indicating an increased risk of NASH progressing tocirrhosis. In one aspect, the one or more biomarkers are outside thenormal range. In one aspect, the one or more biomarkers are above thenormal range but below 2 times the upper limit of the normal range. Inone aspect of this method, the subject has testosterone deficiency. Inone aspect, said subject in need of treatment has testosteronedeficiency with serum testosterone levels of less than 350 ng/dL, 300ng/dL, 250 ng/dL, 200 ng/dL, 150 ng/dL or 100 ng/dL. In one aspect, theone or more biomarkers are above the normal range but between 2-3 timesthe upper limit of the normal range or more. In one aspect, the one ormore biomarkers are above the normal range but below 2 times the upperlimit of the normal range. In one aspect of this method, oraladministration of the testosterone ester reduces the progression of NASHto cirrhosis while not substantially increasing serum levels of ordecreases serum levels of lipoprotein-associated phospholipase A2. Inone aspect, said method increases said subject's serum testosteronelevels over their baseline. In another aspect said method increases saidsubject's serum testosterone levels into the normal range. In oneaspect, said method comprise oral administration of 200 mg to 750 mg oftestosterone undecanoate per day to a male subject. In one aspect, saidmethod comprises oral administration of 300 mg to 600 mg of testosteroneundecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of 450 mg of testosterone undecanoate perday to a male subject. In one aspect, said method comprises oraladministration of about 400 mg to 2000 mg of testosterone tridecanoateper day to a male subject. In one aspect, said method comprises oraladministration of about 600 mg to 1800 mg of testosterone tridecanoateper day to a male subject. In one aspect, said method comprises oraladministration of about 500 mg, 750 mg, 1000 mg, or 1250 mg oftestosterone tridecanoate per day to a male subject. These dose rangesare typically those for male subjects whereas the female dose rangecorresponds to about 1/10^(th)- 1/15^(th) of these values. In one aspectthe subject is from 18-25 years old, 26-35 years old, 36-45 years old,45-55 years old, 56-65 years old or older than 65 years old. In oneaspect, the biomarker is one or more chosen from ALP, ALT, AST, GGT,triglycerides, LDL, cholesterol, liver biopsy, inflammation biomarkers,non-HDL cholesterol, hematocrit, hemoglobin, lipoprotein phospholipaseA2, bilirubin, albumin, SHBG, any specific biomarkers disclosed in theTables of Example 1, imaging biomarkers, liver histology biomarkers,biomarkers in the literature related to the disease and conditiondescribed herein, and liver damage biomarkers. In one aspect of thisembodiment, the subject has one or more of the following comorbidities:obesity, type 2 diabetes, dyslipidemia, cardiovascular disease, thyroiddysfunction, chronic kidney disease, liver disease, osteoporosis,hypogonadism, hypertension, sarcopenia, or cachexia.

In an embodiment, a method for treating a subject at risk of havingsteatosis progressing to cirrhosis is provided said method comprisingoral administration of a pharmaceutical composition having atestosterone ester (e.g., testosterone undecanoate or testosteronetridecanoate) to said subject. In one aspect, the subject is in need oftreatment. In one aspect, the subject in need of treatment has one ormore biomarkers (or clinical characteristics) indicating an increasedrisk of steatosis progressing to cirrhosis. In one aspect, the one ormore biomarkers are outside the normal range. In one aspect, the one ormore biomarkers are above the normal range but below 2 times the upperlimit of the normal range. In one aspect of this method, the subject hastestosterone deficiency. In one aspect, said subject in need oftreatment has testosterone deficiency with serum testosterone levels ofless than 350 ng/dL, 300 ng/dL, 250 ng/dL, 200 ng/dL, 150 ng/dL or 100ng/dL. In one aspect, the one or more biomarkers are above the normalrange but between 2-3 times the upper limit of the normal range or more.In one aspect, the one or more biomarkers are above the normal range butbelow 2 times the upper limit of the normal range. In one aspect of thismethod, oral administration of the testosterone ester reduces the riskof steatosis progressing to cirrhosis while not substantially increasingserum levels of or decreases serum levels of lipoprotein-associatedphospholipase A2. In one aspect, said method increases said subject'sserum testosterone levels over their baseline. In another aspect saidmethod increases said subject's serum testosterone levels into thenormal range. In one aspect, said method comprises oral administrationof 200 mg to 750 mg of testosterone undecanoate per day to a malesubject. In one aspect, said method comprises oral administration of 300mg to 600 mg of testosterone undecanoate per day to a male subject. Inone aspect, said method comprises oral administration of 450 mg oftestosterone undecanoate per day to a male subject. In one aspect, saidmethod comprises oral administration of about 400 mg to 2000 mg oftestosterone tridecanoate per day to a male subject. In one aspect, saidmethod comprises oral administration of about 600 mg to 1800 mg oftestosterone tridecanoate per day to a male subject. In one aspect, saidmethod comprises oral administration of about 500 mg, 750 mg, 1000 mg,or 1250 mg of testosterone tridecanoate per day to a male subject. Thesedose ranges are typically those for male subjects whereas the femaledose range corresponds to about 1/10^(th)- 1/15^(th) of these values. Inone aspect the subject is from 18-25 years old, 26-35 years old, 36-45years old, 45-55 years old, 56-65 years old or older than 65 years old.In one aspect, the biomarker is one or more chosen from ALP, ALT, AST,GGT, triglycerides, LDL, cholesterol, liver biopsy, inflammationbiomarkers, non-HDL cholesterol, hematocrit, hemoglobin, lipoproteinphospholipase A2, bilirubin, albumin, SHBG, any specific biomarkersdisclosed in the Tables of Example 1, imaging biomarkers, liverhistology biomarkers, biomarkers in the literature related to thedisease and condition described herein, and liver damage biomarkers. Inone aspect of this embodiment, the subject has one or more of thefollowing comorbidities: obesity, type 2 diabetes, dyslipidemia,cardiovascular disease, thyroid dysfunction, chronic kidney disease,liver disease, osteoporosis, hypogonadism, hypertension, sarcopenia, orcachexia.

In one embodiment, a method for improving survival of a subject waitingfor a liver transplant or decreasing mortality is provided said methodcomprising oral administration of a pharmaceutical composition having atestosterone ester (e.g., testosterone undecanoate or testosteronetridecanoate) to a subject in need of treatment. In one aspect, thesubject is in need of treatment e.g., is on a liver transplant waitinglist or is in need of a liver transplant. In one aspect, the subject inneed of treatment has one or more biomarkers (or clinicalcharacteristics) indicating compromised survival. In one aspect, the oneor more biomarkers are outside the normal range. In one aspect, the oneor more biomarkers are above the normal range but below 2 times theupper limit of the normal range. In one aspect of this method, thesubject has testosterone deficiency. In one aspect, said subject in needof treatment has testosterone deficiency with serum testosterone levelsof less than 350 ng/dL, 300 ng/dL, 250 ng/dL, 200 ng/dL, 150 ng/dL or100 ng/dL. In one aspect, the one or more biomarkers are above thenormal range but between 2-3 times the upper limit of the normal rangeor more. In one aspect, the one or more biomarkers are above the normalrange but below 2 times the upper limit of the normal range. In oneaspect of this method, oral administration of the testosterone esterimproves the survival (e.g., reduces mortality) of subjects while notsubstantially increasing serum levels of or decreases serum levels oflipoprotein-associated phospholipase A2. In one aspect, said methodincreases said subject's serum testosterone levels over their baseline.In another aspect said method increases said subject's serumtestosterone levels into the normal range. In one aspect, said methodcomprise oral administration of 200 mg to 750 mg of testosteroneundecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of 300 mg to 600 mg of testosteroneundecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of 450 mg of testosterone undecanoate perday to a male subject. In one aspect, said method comprises oraladministration of about 400 mg to 2000 mg of testosterone tridecanoateper day to a male subject. In one aspect, said method comprises oraladministration of about 600 mg to 1800 mg of testosterone tridecanoateper day to a male subject. In one aspect, said method comprises oraladministration of about 500 mg, 750 mg, 1000 mg, or 1250 mg oftestosterone tridecanoate per day to a male subject. These dose rangesare typically those for male subjects whereas the female dose rangecorresponds to about 1/10^(th)- 1/15^(th) of these values. In one aspectthe subject is from 18-25 years old, 26-35 years old, 36-45 years old,45-55 years old, 56-65 years old or older than 65 years old. In oneaspect, the biomarker is one or more chosen from ALP, ALT, AST, GGT,triglycerides, LDL, cholesterol, liver biopsy, inflammation biomarkers,non-HDL cholesterol, hematocrit, hemoglobin, lipoprotein phospholipaseA2, bilirubin, albumin, SHBG, any specific biomarkers disclosed in theTables of Example 1, imaging biomarkers, liver histology biomarkers,biomarkers in the literature related to the disease and conditiondescribed herein, and liver damage biomarkers. In one aspect of thisembodiment, the subject has one or more of the following comorbidities:obesity, type 2 diabetes, dyslipidemia, cardiovascular disease, thyroiddysfunction, chronic kidney disease, liver disease, osteoporosis,hypogonadism, hypertension, sarcopenia, or cachexia.

In an embodiment, a method of improving serum alkaline phosphataselevels in a subject is provided said method comprising oraladministration of a pharmaceutical composition having a testosteroneester (e.g., testosterone undecanoate or testosterone tridecanoate) tosaid subject in need of treatment (e.g., having liver disease or at riskof having liver disease). In one aspect, the subject in need oftreatment has one or more biomarkers (or clinical characteristics)indicating a need for reduction in alkaline phosphatase levels. In oneaspect, the one or more biomarkers are outside the normal range. In oneaspect, the one or more biomarkers are above the normal range but below2 times the upper limit of the normal range. In one aspect of thismethod, the subject has testosterone deficiency. In one aspect, saidsubject in need of treatment has testosterone deficiency with serumtestosterone levels of less than 350 ng/dL, 300 ng/dL, 250 ng/dL, 200ng/dL, 150 ng/dL or 100 ng/dL. In one aspect, the one or more biomarkersare above the normal range but between 2-3 times the upper limit of thenormal range or more. In one aspect, the one or more biomarkers areabove the normal range but below 2 times the upper limit of the normalrange. In one aspect of this method, oral administration of thetestosterone ester improves serum alkaline phosphatase levels while notsubstantially increasing serum levels of or decreases serum levels oflipoprotein-associated phospholipase A2. In one aspect, said methodincreases said subject's serum testosterone levels over their baseline.In another aspect said method increases said subject's serumtestosterone levels into the normal range. In one aspect, said methodcomprises oral administration of 200 mg to 750 mg of testosteroneundecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of 300 mg to 600 mg of testosteroneundecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of 450 mg of testosterone undecanoate perday to a male subject. In one aspect, said method comprises oraladministration of about 400 mg to 2000 mg of testosterone tridecanoateper day to a male subject. In one aspect, said method comprises oraladministration of about 600 mg to 1800 mg of testosterone tridecanoateper day to a male subject. In one aspect, said method comprises oraladministration of about 500 mg, 750 mg, 1000 mg, or 1250 mg oftestosterone tridecanoate per day to a male subject. These dose rangesare typically those for male subjects whereas the female dose rangecorresponds to about 1/10^(th)- 1/15^(th) of these values. In one aspectthe subject is from 18-25 years old, 26-35 years old, 36-45 years old,45-55 years old, 56-65 years old or older than 65 years old. In oneaspect, the biomarker is one or more chosen from ALP, ALT, AST, GGT,triglycerides, LDL, cholesterol, liver biopsy, inflammation biomarkers,non-HDL cholesterol, hematocrit, hemoglobin, lipoprotein phospholipaseA2, bilirubin, albumin, SHBG, any specific biomarkers disclosed in theTables of Example 1, imaging biomarkers, liver histology biomarkers,biomarkers in the literature related to the disease and conditiondescribed herein, and liver damage biomarkers. In one aspect of thisembodiment, the subject has one or more of the following comorbidities:obesity, type 2 diabetes, dyslipidemia, cardiovascular disease, thyroiddysfunction, chronic kidney disease, liver disease, osteoporosis,hypogonadism, hypertension, sarcopenia, or cachexia.

In another embodiment, a method for improving serum alanineaminotransferase levels in a subject is provided said method comprisingoral administration of a pharmaceutical composition having atestosterone ester (e.g., testosterone undecanoate or testosteronetridecanoate) to said subject. In one aspect, the subject is in need oftreatment (e.g., has liver disease or is at risk of having liverdisease). In one aspect, the subject in need of treatment has one ormore biomarkers (or clinical characteristics) indicating a need forimproving serum aminotransferase levels. In one aspect, the one or morebiomarkers are outside the normal range. In one aspect, the one or morebiomarkers are above the normal range but below 2 times the upper limitof the normal range. In one aspect of this method, the subject hastestosterone deficiency. In one aspect, the one or more biomarkers areabove the normal range but between 2-3 times the upper limit of thenormal range or more. In one aspect, the one or more biomarkers areabove the normal range but below 2 times the upper limit of the normalrange. In one aspect of this method, the subject has testosteronedeficiency. In one aspect, said subject in need of treatment hastestosterone deficiency with serum testosterone levels of less than 350ng/dL, 300 ng/dL, 250 ng/dL, 200 ng/dL, 150 ng/dL or 100 ng/dL. In oneaspect of this method, oral administration of the testosterone esterimproves serum alanine transaminase levels while not substantiallyincreasing serum levels of or decreases serum levels oflipoprotein-associated phospholipase A2. In one aspect, said methodincreases said subject's serum testosterone levels over their baseline.In another aspect said method increases said subject's serumtestosterone levels into the normal range. In one aspect, said methodcomprises oral administration of 200 mg to 750 mg of testosteroneundecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of 300 mg to 600 mg of testosteroneundecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of 450 mg of testosterone undecanoate perday to a male subject. In one aspect, said method comprises oraladministration of about 400 mg to 2000 mg of testosterone tridecanoateper day to a male subject. In one aspect, said method comprises oraladministration of about 600 mg to 1800 mg of testosterone tridecanoateper day to a male subject. In one aspect, said method comprises oraladministration of about 500 mg, 750 mg, 1000 mg, or 1250 mg oftestosterone tridecanoate per day to a male subject. These dose rangesare typically those for male subjects whereas the female dose rangecorresponds to about 1/10^(th)- 1/15^(th) of these values. In oneaspect, the subject is from 18-25 years old, 26-35 years old, 36-45years old, 45-55 years old, 56-65 years old or older than 65 years old.In one aspect, the biomarker is one or more chosen from ALP, ALT, AST,GGT, triglycerides, LDL, cholesterol, liver biopsy, inflammationbiomarkers, non-HDL cholesterol, hematocrit, hemoglobin, lipoproteinphospholipase A2, bilirubin, albumin, SHBG, any specific biomarkersdisclosed in the Tables of Example 1, imaging biomarkers, liverhistology biomarkers, biomarkers in the literature related to thedisease and condition described herein, and liver damage biomarkers. Inone aspect of this embodiment, the subject has one or more of thefollowing comorbidities: obesity, type 2 diabetes, cardiovasculardisease, thyroid dysfunction, chronic kidney disease, liver disease,osteoporosis, hypogonadism, hypertension, sarcopenia, or cachexia.

In yet another embodiment, a method for improving serum aspartateaminotransaminase levels in a subject is provided said method comprisingoral administration of a pharmaceutical composition having atestosterone ester (e.g., testosterone undecanoate or testosteronetridecanoate) to said subject. In one aspect, the subject is in need oftreatment (has liver disease or is at risk of having liver disease). Inone aspect, the subject in need of treatment has one or more biomarkers(or clinical characteristics) indicating a need for improving serumaspartate aminotransaminase levels. In one aspect, the one or morebiomarkers are outside the normal range. In one aspect, the one or morebiomarkers are above the normal range but below 2 times the upper limitof the normal range. In one aspect of this method, the subject hastestosterone deficiency. In one aspect, said subject in need oftreatment has testosterone deficiency with serum testosterone levels ofless than 350 ng/dL, 300 ng/dL, 250 ng/dL, 200 ng/dL, 150 ng/dL or 100ng/dL. In one aspect, the one or more biomarkers are above the normalrange but between 2-3 times the upper limit of the normal range or more.In one aspect, the one or more biomarkers are above the normal range butbelow 2 times the upper limit of the normal range. In one aspect of thismethod, oral administration of the testosterone ester reduces the riskof steatosis progressing to cirrhosis while not substantially increasingserum levels of or decreases serum levels of lipoprotein-associatedphospholipase A2. In one aspect, said method increases said subject'sserum testosterone levels over their baseline. In another aspect, saidmethod increases said subject's serum testosterone levels into thenormal range. In one aspect, said method comprises oral administrationof 200 mg to 750 mg of testosterone undecanoate per day to a malesubject. In one aspect, said method comprises oral administration of 300mg to 600 mg of testosterone undecanoate per day to a male subject. Inone aspect, said method comprises oral administration of 450 mg oftestosterone undecanoate per day to a male subject. In one aspect, saidmethod comprises oral administration of about 400 mg to 2000 mg oftestosterone tridecanoate per day to a male subject. In one aspect, saidmethod comprises oral administration of about 600 mg to 1800 mg oftestosterone tridecanoate per day to a male subject. In one aspect, saidmethod comprises oral administration of about 500 mg, 750 mg, 1000 mg,or 1250 mg of testosterone tridecanoate per day to a male subject. Thesedose ranges are typically those for male subjects whereas the femaledose range corresponds to about 1/10^(th)- 1/15^(th) of these values. Inone aspect the subject is from 18-25 years old, 26-35 years old, 36-45years old, 46-55 years old, 56-65 years old or older than 65 years old.In one aspect, the biomarker is one or more chosen from ALP, ALT, AST,GGT, triglycerides, LDL, cholesterol, liver biopsy, inflammationbiomarkers, non-HDL cholesterol, hematocrit, hemoglobin, lipoproteinphospholipase A2, bilirubin, albumin, SHBG, any specific biomarkersdisclosed in the Tables of Example 1, imaging biomarkers, liverhistology biomarkers, biomarkers in the literature related to thedisease and condition described herein, and liver damage biomarkers. Inone aspect of this embodiment, the subject has one or more of thefollowing comorbidities: obesity, type 2 diabetes, dyslipidemia,cardiovascular disease, thyroid dysfunction, chronic kidney disease,liver disease, osteoporosis, hypogonadism, hypertension, sarcopenia, orcachexia.

In another embodiment, a method for treating or preventing hepaticsteatosis in a subject is provided said method comprising oraladministration of a pharmaceutical composition having a testosteroneester (e.g., testosterone undecanoate or testosterone tridecanoate) tosaid subject. In one aspect, the subject is in need of treatment (e.g.,has liver disease or is at risk of having liver disease). In one aspect,the subject in need of treatment has one or more biomarkers (or clinicalcharacteristics) indicating an increased risk of hepatic steatosis. Inone aspect, the one or more biomarkers are outside the normal range. Inone aspect, the one or more biomarkers are above the normal range butbelow 2 times the upper limit of the normal range. In one aspect of thismethod, the subject has testosterone deficiency. In one aspect, saidsubject in need of treatment has testosterone deficiency with serumtestosterone levels of less than 350 ng/dL, 300 ng/dL, 250 ng/dL, 200ng/dL, 150 ng/dL or 100 ng/dL. In one aspect, the one or more biomarkersare above the normal range but between 2-3 times the upper limit of thenormal range or more. In one aspect, the one or more biomarkers areabove the normal range but below 2 times the upper limit of the normalrange. In one aspect, said method increases said subject's serumtestosterone levels over their baseline. In another aspect, said methodincreases said subject's serum testosterone levels into the normalrange. In one aspect, said method comprises oral administration of 200mg to 750 mg of testosterone undecanoate per day to a male subject. Inone aspect, said method comprises oral administration of 300 mg to 600mg of testosterone undecanoate per day to a male subject. In one aspect,said method comprises oral administration of 450 mg of testosteroneundecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of about 400 mg to 2000 mg of testosteronetridecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of about 600 mg to 1800 mg of testosteronetridecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of about 500 mg, 750 mg, 1000 mg, or 1250mg of testosterone tridecanoate per day to a male subject. These doseranges are typically those for male subjects whereas the female doserange corresponds to about 1/10^(th)- 1/15^(th) of these values. In oneaspect the subject is from 18-25 years old, 26-35 years old, 36-45 yearsold, 45-55 years old, 56-65 years old or older than 65 years old. In oneaspect, the biomarker is one or more chosen from ALP, ALT, AST, GGT,triglycerides, LDL, cholesterol, liver biopsy, inflammation biomarkers,non-HDL cholesterol, hematocrit, hemoglobin, lipoprotein phospholipaseA2, bilirubin, albumin, SHBG, any specific biomarkers disclosed in theTables of Example 1, imaging biomarkers, liver histology biomarkers,biomarkers in the literature related to the disease and conditiondescribed herein, and liver damage biomarkers. In one aspect of thisembodiment, the subject has one or more of the following comorbidities:obesity, type 2 diabetes, dyslipidemia, cardiovascular disease, thyroiddysfunction, chronic kidney disease, liver disease, osteoporosis,hypogonadism, hypertension, sarcopenia, or cachexia.

In one embodiment, a method of improving the ratio of serum alkalinephosphatase levels to (a) aspartate aminotransaminase levels, (b)alanine aminotransferase or (c) both (b) and (c) in a subject isprovided said method comprising oral administration of a pharmaceuticalcomposition having a testosterone ester (e.g., testosterone undecanoateor testosterone tridecanoate) to said subject. In one aspect, thesubject is in need of treatment (has liver disease or is at risk ofhaving liver disease). In one aspect, the subject in need of treatmenthas one or more biomarkers (or clinical characteristics) indicating aneed for improving the ratio of serum alkaline phosphatase levels to (a)aspartate aminotransaminase levels, (b) alanine aminotransferase or (c)both (b) and (c). In one aspect, the one or more biomarkers are outsidethe normal range. In one aspect, the one or more biomarkers are abovethe normal range but below 2 times the upper limit of the normal range.In one aspect of this method, the subject has testosterone deficiency.In one aspect, said subject in need of treatment has testosteronedeficiency with serum testosterone levels of less than 350 ng/dL, 300ng/dL, 250 ng/dL, 200 ng/dL, 150 ng/dL or 100 ng/dL. In one aspect, theone or more biomarkers are above the normal range but between 2-3 timesthe upper limit of the normal range or more. In one aspect, the one ormore biomarkers are above the normal range but below 2 times the upperlimit of the normal range. In one aspect of this method, the subject hastestosterone deficiency. In one aspect of this method, oraladministration of the testosterone ester improves serum aspartatetransaminase levels while not substantially increasing serum levels ofor decreases serum levels of lipoprotein-associated phospholipase A2. Inone aspect, said method increases said subject's serum testosteronelevels over their baseline. In another aspect, said method increasessaid subject's serum testosterone levels into the normal range. In oneaspect, said method comprises oral administration of 200 mg to 750 mg oftestosterone undecanoate per day to a male subject. In one aspect, saidmethod comprises oral administration of 300 mg to 600 mg of testosteroneundecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of 450 mg of testosterone undecanoate perday to a male subject. In one aspect, said method comprises oraladministration of about 400 mg to 2000 mg of testosterone tridecanoateper day to a male subject. In one aspect, said method comprises oraladministration of about 600 mg to 1800 mg of testosterone tridecanoateper day to a male subject. In one aspect, said method comprises oraladministration of about 500 mg, 750 mg, 1000 mg, or 1250 mg oftestosterone tridecanoate per day to a male subject. These dose rangesare typically those for male subjects whereas the female dose rangecorresponds to about 1/10^(th)- 1/15^(th) of these values. In one aspectthe subject is from 18-25 years old, 26-35 years old, 36-45 years old,46-55 years old, 56-65 years old or older than 65 years old. In oneaspect, the biomarker is one or more chosen from ALP, ALT, AST, GGT,triglycerides, LDL, cholesterol, liver biopsy, inflammation biomarkers,non-HDL cholesterol, hematocrit, hemoglobin, lipoprotein phospholipaseA2, bilirubin, albumin, SHBG, any specific biomarkers disclosed in theTables of Example 1, imaging biomarkers, liver histology biomarkers,biomarkers in the literature related to the disease and conditiondescribed herein, and liver damage biomarkers. In one aspect of thisembodiment, the subject has one or more of the following comorbidities:obesity, type 2 diabetes, dyslipidemia, cardiovascular disease, thyroiddysfunction, chronic kidney disease, liver disease, osteoporosis,hypogonadism, hypertension, sarcopenia, or cachexia.

In yet another embodiment, a method of treating anemia in a subject isprovided said method comprising oral administration of a pharmaceuticalcomposition having a testosterone ester (e.g., testosterone undecanoateor testosterone tridecanoate) to said subject in need of treatment(e.g., has liver disease or is at risk of having liver disease). In oneaspect of this method, the subject has testosterone deficiency. In oneaspect, said subject in need of treatment has testosterone deficiencywith serum testosterone levels of less than 350 ng/dL, 300 ng/dL, 250ng/dL, 200 ng/dL, 150 ng/dL or 100 ng/dL. In one aspect of this method,oral administration of the testosterone ester treats anemia in a subjecthaving liver disease while not substantially increasing serum levels ofor decreases serum levels of Lipoprotein-associated phospholipase A2. Inone aspect, said method increases said subject's serum testosteronelevels over their baseline. In another aspect, said method increasessaid subject's serum testosterone levels into the normal range. In oneaspect, said method comprises oral administration of 200 mg to 750 mg oftestosterone undecanoate per day to a male subject. In one aspect, saidmethod comprises oral administration of 300 mg to 600 mg of testosteroneundecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of 450 mg of testosterone undecanoate perday to a male subject. In one aspect, said method comprises oraladministration of about 400 mg to 2000 mg of testosterone tridecanoateper day to a male subject. In one aspect, said method comprises oraladministration of about 600 mg to 1800 mg of testosterone tridecanoateper day to a male subject. In one aspect, said method comprises oraladministration of about 500 mg, 750 mg, 1000 mg, or 1250 mg oftestosterone tridecanoate per day to a male subject. These dose rangesare typically those for male subjects whereas the female dose rangecorresponds to about 1/10^(th)- 1/15^(th) of these values. In one aspectthe subject is from 18-25 years old, 26-35 years old, 36-45 years old,45-55 years old, 56-65 years old or older than 65 years old. In oneaspect, the biomarker is one or more chosen from ALP, ALT, AST, GGT,triglycerides, LDL, cholesterol, liver biopsy, inflammation biomarkers,non-HDL cholesterol, hematocrit, hemoglobin, lipoprotein phospholipaseA2, bilirubin, albumin, SHBG, any specific biomarkers disclosed in theTables of Example 1, imaging biomarkers, liver histology biomarkers,biomarkers in the literature related to the disease and conditiondescribed herein, and liver damage biomarkers. In one aspect of thisembodiment, the subject has one or more of the following comorbidities:obesity, type 2 diabetes, dyslipidemia, cardiovascular disease, thyroiddysfunction, chronic kidney disease, liver disease, osteoporosis,hypogonadism, hypertension, sarcopenia, or cachexia.

In again another embodiment, a method of treating graft rejection in asubject is provided said method comprising oral administration of apharmaceutical composition having a testosterone ester (e.g.,testosterone undecanoate or testosterone tridecanoate) to said subject(e.g., has received a liver transplant). In one aspect of this method,the subject has testosterone deficiency. In one aspect, said subject inneed of treatment has testosterone deficiency with serum testosteronelevels of less than 350 ng/dL, 300 ng/dL, 250 ng/dL, 200 ng/dL, 150ng/dL or 100 ng/dL. In one aspect, the subject in need of treatment hasone or more biomarkers (or clinical characteristics) indicating anincreased risk of graft rejection. In one aspect, the one or morebiomarkers are outside the normal range. In one aspect, the one or morebiomarkers are above the normal range but below 2 times the upper limitof the normal range. In one aspect, the one or more biomarkers are abovethe normal range but between 2-3 times the upper limit of the normalrange or more. In one aspect, the one or more biomarkers are above thenormal range but below 2 times the upper limit of the normal range. Inone aspect of this method, oral administration of the testosterone estertreats graft rejection while not substantially increasing serum levelsof or decreases serum levels of lipoprotein-associated phospholipase A2.In one aspect, said method increases said subject's serum testosteronelevels over their baseline. In another aspect said method increases saidsubject's serum testosterone levels into the normal range. In oneaspect, said method comprise oral administration of 200 mg to 750 mg oftestosterone undecanoate per day to a male subject. In one aspect, saidmethod comprises oral administration of 300 mg to 600 mg of testosteroneundecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of 450 mg of testosterone undecanoate perday to a male subject. In one aspect, said method comprises oraladministration of about 400 mg to 2000 mg of testosterone tridecanoateper day to a male subject. In one aspect, said method comprises oraladministration of about 600 mg to 1800 mg of testosterone tridecanoateper day to a male subject. In one aspect, said method comprises oraladministration of about 500 mg, 750 mg, 1000 mg, or 1250 mg oftestosterone tridecanoate per day to a male subject. These dose rangesare typically those for male subjects whereas the female dose rangecorresponds to about 1/10^(th)- 1/15^(th) of these values. In one aspectthe subject is from 18-25 years old, 26-35 years old, 36-45 years old,45-55 years old, 56-65 years old or older than 65 years old. In oneaspect, the biomarker is one or more chosen from ALP, ALT, AST, GGT,triglycerides, LDL, cholesterol, liver biopsy, inflammation biomarkers,non-HDL cholesterol, hematocrit, hemoglobin, lipoprotein phospholipaseA2, bilirubin, albumin, SHBG, any specific biomarkers disclosed in theTables of Example 1, imaging biomarkers, liver histology biomarkers,biomarkers in the literature related to the disease and conditiondescribed herein, and liver damage biomarkers. In one aspect of thisembodiment, the subject has one or more of the following comorbidities:obesity, type 2 diabetes, dyslipidemia, cardiovascular disease, thyroiddysfunction, chronic kidney disease, liver disease, osteoporosis,hypogonadism, hypertension, sarcopenia, or cachexia.

In another embodiment, a method of treating alcoholic steatosis in asubject is provided said method comprising oral administration of apharmaceutical composition having a testosterone ester (e.g.,testosterone undecanoate or testosterone tridecanoate) to said subject.In one aspect of this method, the subject has testosterone deficiency.In one aspect, said subject in need of treatment has testosteronedeficiency with serum testosterone levels of less than 350 ng/dL, 300ng/dL, 250 ng/dL, 200 ng/dL, 150 ng/dL or 100 ng/dL. In one aspect, thesubject in need of treatment has one or more biomarkers (or clinicalcharacteristics) related to alcoholic steatosis. In one aspect, saidsubject is in need of treatment e.g., has an increased risk of alcoholicsteatosis or progression of alcoholic steatosis. In one aspect, the oneor more biomarkers are outside the normal range. In one aspect, the oneor more biomarkers are above the normal range but below 2 times theupper limit of the normal range. In one aspect of this method, thesubject has testosterone deficiency. In one aspect, the one or morebiomarkers are above the normal range but between 2-3 times the upperlimit of the normal range or more. In one aspect, the one or morebiomarkers are above the normal range but below 2 times the upper limitof the normal range. In one aspect of this method, oral administrationof the testosterone ester treats alcoholic steatosis while notsubstantially increasing serum levels of or decreases serum levels ofLipoprotein-associated phospholipase A2. In one aspect, said methodincreases said subject's serum testosterone levels over their baseline.In another aspect said method increases said subject's serumtestosterone levels into the normal range. In one aspect, said methodcomprises oral administration of 200 mg to 750 mg of testosteroneundecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of 300 mg to 600 mg of testosteroneundecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of 450 mg of testosterone undecanoate perday to a male subject. In one aspect, said method comprises oraladministration of about 400 mg to 2000 mg of testosterone tridecanoateper day to a male subject. In one aspect, said method comprises oraladministration of about 600 mg to 1800 mg of testosterone tridecanoateper day to a male subject. In one aspect, said method comprises oraladministration of about 500 mg, 750 mg, 1000 mg, or 1250 mg oftestosterone tridecanoate per day to a male subject. These dose rangesare typically those for male subjects whereas the female dose rangecorresponds to about 1/10^(th)- 1/15^(th) of these values. In one aspectthe subject is from 18-25 years old, 26-35 years old, 36-45 years old,45-55 years old, 56-65 years old or older than 65 years old. In oneaspect, the biomarker is one or more chosen from ALP, ALT, AST, GGT,triglycerides, LDL, cholesterol, liver biopsy, inflammation biomarkers,non-HDL cholesterol, hematocrit, hemoglobin, lipoprotein phospholipaseA2, bilirubin, albumin, SHBG, any specific biomarkers disclosed in theTables of Example 1, imaging biomarkers, liver histology biomarkers,biomarkers in the literature related to the disease and conditiondescribed herein, and liver damage biomarkers. In one aspect of thisembodiment, the subject has one or more of the following comorbidities:obesity, type 2 diabetes, dyslipidemia, cardiovascular disease, thyroiddysfunction, chronic kidney disease, liver disease, osteoporosis,hypogonadism, hypertension, sarcopenia, or cachexia.

In another embodiment, a method of treating alcoholic cirrhosis in asubject is provided said method comprising oral administration of apharmaceutical composition having a testosterone ester (e.g.,testosterone undecanoate or testosterone tridecanoate) to said subject(e.g., having alcoholic cirrhosis). In one aspect of this method, thesubject has testosterone deficiency. In one aspect, said subject in needof treatment has testosterone deficiency with serum testosterone levelsof less than 350 ng/dL, 300 ng/dL, 250 ng/dL, 200 ng/dL, 150 ng/dL or100 ng/dL. In one aspect, the subject in need of treatment has one ormore biomarkers (or clinical characteristics) related to alcoholiccirrhosis. In one aspect, said subject is in need of treatment e.g., hasan increased risk of alcoholic cirrhosis or progression of alcoholiccirrhosis or increased risk of death from alcoholic cirrhosis. In oneaspect, the one or more biomarkers are outside the normal range. In oneaspect, the one or more biomarkers are above the normal range but below2 times the upper limit of the normal range. In one aspect of thismethod, the subject has testosterone deficiency. In one aspect, the oneor more biomarkers are above the normal range but between 2-3 times theupper limit of the normal range or more. In one aspect, the one or morebiomarkers are above the normal range but below 2 times the upper limitof the normal range. In one aspect of this method, oral administrationof the testosterone ester treats alcoholic cirrhosis while notsubstantially increasing serum levels of or decreases serum levels ofLipoprotein-associated phospholipase A2. In one aspect, said methodincreases said subject's serum testosterone levels over their baseline.In another aspect said method increases said subject's serumtestosterone levels into the normal range. In one aspect, said methodcomprises oral administration of 200 mg to 750 mg of testosteroneundecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of 300 mg to 600 mg of testosteroneundecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of 450 mg of testosterone undecanoate perday to a male subject. In one aspect, said method comprises oraladministration of about 400 mg to 2000 mg of testosterone tridecanoateper day to a male subject. In one aspect, said method comprises oraladministration of about 600 mg to 1800 mg of testosterone tridecanoateper day to a male subject. In one aspect, said method comprises oraladministration of about 500 mg, 750 mg, 1000 mg, or 1250 mg oftestosterone tridecanoate per day to a male subject. These dose rangesare typically those for male subjects whereas the female dose rangecorresponds to about 1/10^(th)- 1/15^(th) of these values. In one aspectthe subject is from 18-25 years old, 26-35 years old, 36-45 years old,45-55 years old, 56-65 years old or older than 65 years old. In oneaspect, the biomarker is one or more chosen from ALP, ALT, AST, GGT,triglycerides, LDL, cholesterol, liver biopsy, inflammation biomarkers,non-HDL cholesterol, hematocrit, hemoglobin, lipoprotein phospholipaseA2, bilirubin, albumin, SHBG, any specific biomarkers disclosed in theTables of Example 1, imaging biomarkers, liver histology biomarkers,biomarkers in the literature related to the disease and conditiondescribed herein, and liver damage biomarkers. In one aspect of thisembodiment, the subject has one or more of the following comorbidities:obesity, type 2 diabetes, dyslipidemia, cardiovascular disease, thyroiddysfunction, chronic kidney disease, liver disease, osteoporosis,hypogonadism, hypertension, sarcopenia, or cachexia.

In another embodiment, a method of treating alcoholic liver disease in asubject is provided said method comprising oral administration of apharmaceutical composition having a testosterone ester (e.g.,testosterone undecanoate or testosterone tridecanoate) to said subject.In one aspect of this method, the subject has testosterone deficiency.In one aspect, said subject in need of treatment has testosteronedeficiency with serum testosterone levels of less than 350 ng/dL, 300ng/dL, 250 ng/dL, 200 ng/dL, 150 ng/dL or 100 ng/dL. In one aspect, thesubject in need of treatment has one or more biomarkers (or clinicalcharacteristics) of alcoholic liver disease. In one aspect, said subjectis in need of treatment e.g., has an increased risk of alcoholic liverdisease or progression of alcoholic liver disease or increased risk ofdeath from alcoholic liver disease. In one aspect, the one or morebiomarkers are outside the normal range. In one aspect, the one or morebiomarkers are above the normal range but below 2 times the upper limitof the normal range. In one aspect of this method, the subject hastestosterone deficiency. In one aspect, the one or more biomarkers areabove the normal range but between 2-3 times the upper limit of thenormal range or more. In one aspect, the one or more biomarkers areabove the normal range but below 2 times the upper limit of the normalrange. In one aspect of this method, oral administration of thetestosterone ester treats alcoholic liver disease while notsubstantially increasing serum levels of or decreases serum levels ofLipoprotein-associated phospholipase A2. In one aspect, said methodincreases said subject's serum testosterone levels over their baseline.In another aspect said method increases said subject's serumtestosterone levels into the normal range. In one aspect, said methodcomprises oral administration of 200 mg to 750 mg of testosteroneundecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of 300 mg to 600 mg of testosteroneundecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of 450 mg of testosterone undecanoate perday to a male subject. In one aspect, said method comprises oraladministration of about 400 mg to 2000 mg of testosterone tridecanoateper day to a male subject. In one aspect, said method comprises oraladministration of about 600 mg to 1800 mg of testosterone tridecanoateper day to a male subject. In one aspect, said method comprises oraladministration of about 500 mg, 750 mg, 1000 mg, or 1250 mg oftestosterone tridecanoate per day to a male subject. These dose rangesare typically those for male subjects whereas the female dose rangecorresponds to about 1/10^(th)- 1/15^(th) of these values. In one aspectthe subject is from 18-25 years old, 26-35 years old, 36-45 years old,45-55 years old, 56-65 years old or older than 65 years old. In oneaspect, the biomarker is one or more chosen from ALP, ALT, AST, GGT,triglycerides, LDL, cholesterol, liver biopsy, inflammation biomarkers,non-HDL cholesterol, hematocrit, hemoglobin, lipoprotein phospholipaseA2, bilirubin, albumin, SHBG, any specific biomarkers disclosed in theTables of Example 1, imaging biomarkers, liver histology biomarkers,biomarkers in the literature related to the disease and conditiondescribed herein, and liver damage biomarkers. In one aspect of thisembodiment, the subject has one or more of the following comorbidities:obesity, type 2 diabetes, dyslipidemia, cardiovascular disease, thyroiddysfunction, chronic kidney disease, liver disease, osteoporosis,hypogonadism, hypertension, sarcopenia, or cachexia.

In one aspect, the methods described herein are useful for treating afibrotic condition of the liver. In certain embodiments, the fibroticcondition of the liver is chosen from one or more of: fatty liverdisease, steatosis (e.g., nonalcoholic steatohepatitis (NASH),cholestatic liver disease (e.g., primary biliary cirrhosis (PBC),cirrhosis, alcohol-induced liver fibrosis, biliary duct injury, biliaryfibrosis, cholestasis or cholangiopathies. In some embodiments, hepaticor liver fibrosis includes, but is not limited to, hepatic fibrosisassociated with alcoholism, viral infection, e.g., hepatitis (e.g.,hepatitis C, B or D), autoimmune hepatitis, non-alcoholic fatty liverdisease (NAFLD), progressive massive fibrosis, exposure to toxins orirritants (e.g., alcohol, pharmaceutical drugs and environmentaltoxins).

The methods and compositions described herein are also directed tomethods of inhibiting or reducing the likelihood of liver injury in apatient at risk for same occurring from or secondary to a variety ofetiologies especially including hepatitis (all forms, especiallyincluding hepatitis viral), non-alcoholic fatty liver diseases (NAFLD),including non-alcoholic steatohepatitis (NASH), NAFLD or NASH includingprimary NASH, NASH secondary to liver transplantation (NASH post-livertransplantation), preservation injury of donated organs, acute andchronic liver transplant rejection and metabolic conditions including,for example, Wilson's disease, hemochromatosis, and alpha oneantitrypsin deficiency represent alternative aspects of the presentinvention. In this method, an effective amount of a compositiondescribed herein is administered to a patient at risk for liver injuryas described above in order to inhibit or reduce the likelihood of liverinjury as described above. As a consequence of the actions of compoundsaccording to the present invention in reducing and/or inhibiting liverinjury, certain complications of liver injury may be reduced including,for example, liver failure, liver shock, obstructive jaundice,cirrhosis, including primary biliary cirrhosis, primary sclerosingcholangitis, portal hypertension, ascites, variceal bleeding,encephalopathy, depression, malaise, renal disease, arthritis, portalvein thrombosis, and budd chiari. The present disclosure is alsodirected to treating liver injury and/or reducing the likelihood offurther liver injury associated with or occurring directly from orsecondary to a variety of etiologies especially including hepatitis (allforms), cirrhosis (all types), non-alcoholic fatty liver diseases(NAFLD), including non-alcoholic steatohepatitis (NASH), NAFLD or NASHincluding primary NASH, NASH secondary to liver transplantation (NASHpost-liver transplantation), preservation injury of donated organs,acute and chronic liver transplant rejection and metabolic conditionsincluding, for example, Wilson's disease, hemochromatosis, and alpha oneantitrypsin deficiency. In this method, an effective amount of anandrogen receptor agonist according to the present invention isadministered to a patient with liver injury and/or at risk for furtherliver injury as described above in order to treat, inhibit or reduce thelikelihood of liver injury which occurs directly as a consequence of orsecondary to one or more of the disease states and/or conditions asdescribed above. As a consequence of the treatment methods describedabove, the occurrence and/or severity of one or more of the followingconditions will be substantially reduced: liver failure, liver shock,obstructive jaundice, primary biliary cirrhosis, primary sclerosingcholangitis, portal hypertension, ascites, variceal bleeding,encephalopathy, depression, malaise, renal disease, arthritis, portalvein thrombosis and budd chiari.

As the skilled artisan readily recognizes the embodiments disclosedherein can be adapted to pediatric subjects e.g., subjects less than 18years old. The doses of active ingredients used can be adjustedaccordingly depending on the age and sex of the subject.

In any of the methods disclosed herein, the step of identifying asubject in need of treatment can include the step of determining thenumber of CAG or GGN repeats in the subject's androgen receptor gene.The skilled artisan is capable of using this information for identifyingsubjects in need of treatment, providing specific doses of the androgenreceptor agonists (e.g., testosterone undecanoate or testosteronetridecanoate), or both, as described herein.

Without wishing to be bound by theory, it is believed that is someaspects of the embodiments described herein, the method and compositionscan normalize ratios of serum testosterone to estradiol. Thus, in someaspects, subjects are believed to have a testosterone to estradiol ratioimbalance which can be treated, and therefore become more normal.

Without wishing to be bound by theory, it is believed that is someaspects of the embodiments described herein, the methods andcompositions described herein exerted surprising or expected effects inliver and related disease because they are delivered orally e.g.,perorally, and absorbed via the intestinal lymphatic system. It iscontemplated that delivery via the intestinal lymphatic system providessurprising or unexpected results due to one or more of the following:effects in the lymphatic or interstitial compartment, improved deliveryto target tissues or cells (e.g., one or more of fat, adipocytes,preadipocytes, liver, liver cells, hepatocytes, adipose, white bloodcells, red blood cells, stem cells, bone, bone cells, stem cells,androgen receptor cells, non-androgen receptor containing cells, cellsinvolved in glucose metabolism, and cells involved in fatty acidmetabolism). Thus, in some specific aspects, delivery of thecompositions via the methods disclosed herein results in transport ofthe active agent (e.g., testosterone ester) via intestinal lymphatics,chylomicrons, chylomicron remnants to specific target tissues and cellsto exert or provide the unexpected or surprising results describedherein.

In some aspects of the method embodiments described herein, thetreatments with oral testosterone esters in testosterone deficientsubjects, raise the subject's serum testosterone levels over baseline ore.g., into the normal or eugonadal range for from 0-2 hours, 2-4 hours,4-6 hours, 6-8 hours, 8-10 hours, 10-12-hour, 12-14 hours, 14-18 hours,18-20 hours, 20-22 hours, or 22-24 hours per day.

Combination Therapy

In some embodiments of the methods disclosed herein, the oraltestosterone ester therapy is in conjunction with another therapeutictreatment. In one aspect, the oral testosterone therapy is administeredwith one or more additional therapeutic agents (not necessarily at thesame time or frequency as the oral testosterone ester therapy orandrogen receptor agonist therapy). In some embodiments the one or moreadditional therapeutic agent is a statin. In some embodiments the statinis atorvastatin, rosuvastatin, simvastatin, pravastatin, lovastatin,fluvastatin, or pitavastatin. In one aspect, the amount of atorvastatinadministered per day is from about 10 mg to about 60 mg. In one aspect,the amount of rosuvastatin administered per day is from about 5 mg toabout 20 mg. In one aspect, the amount of simvastatin administered perday is from about 10 mg to about 40 mg. In one aspect, the amount ofpravastatin administered per day is from about 10 mg to about 80 mg.

In one aspect, the amount of lovastatin administered per day is fromabout 20 mg to about 40 mg. In one aspect, the amount of fluvastatinadministered per day is from about 20 mg to about 80 mg. In one aspect,the amount of pitavastatin administered per day is from about 1 mg toabout 4 mg. In one aspect, the amount of atorvastatin is from about 10mg to about 40 mg. In one aspect, amount of rosuvastatin is from about10 to about 20 mg. In one aspect, the amount of simvastatin is fromabout 10 mg to about 20 mg. In one aspect, the amount of pravastatin isfrom about 10 mg to about 20 mg. In one aspect, the amount of lovastatinis about 40 mg. In one aspect, the amount of fluvastatin is from about20 mg to about 40 mg. In one aspect, the amount of pitavastatin is fromabout 1 mg to about 3 mg.

Combination therapies can include administration of more or more of thefollowing: a FXR agonist, a PPAR alpha ordelta agent, a lipid modulator,an anti-inflammatory (e.g., steroidal or non-steroidal anti-inflammatoryagents or other), an antioxidant, an immunomodulator, an insulinsenitizer, an incretin mimetic, a hemorrheologic agent, an inhibitor ofapoptosis, an agonist of the peroxisome proliferator, a thyroid hormonereceptor modulator, an ASK1 inhibitor, an Acetyl-CoA Carboxylase (ACC)inhibitor, a fatty-acid/bile-acid Conjugate, galectin inhibitor, caspaseprotease inhibitor or a combination thereof in conjunction with theandrogen receptor agonist (e.g., testosterone ester like testosteroneundecanoate or testosterone tridecanoate).

The present disclosure is also directed to methods of treating hepatitis(all types, including non-alcoholic steatohepatitis (NASH)), cirrhosis(all types), fatty liver disease, including non-alcoholic fatty liverdisease (NAFLD), including cirrhosis in a patient at risk, primary NASHor NASH secondary to liver transplantation, by administering aneffective amount of an androgen receptor agonist compound as otherwisedescribed hereinabove to said patient. In this aspect, a method fortreating NAFLD, NASH including primary NASH, cirrhosis and/or NASHsecondary to liver transplantation (NASH post-liver transplantation)comprises orally administering to a patient in need thereof an effectiveamount of a testosterone ester (e.g., testosterone undecanoate,testosterone tridecanoate, or a combination thereof) and vitamin E, avitamin E prodrug or a vitamin E derivative, as otherwise disclosedherein, optionally in combination with a carrier, additive or excipient.In treating the above disease states and/or conditions there is aninhibition or a reduction in the likelihood of liver injury or that oneor more of the following conditions will occur in the treated patient:liver failure, portal hypertension, ascites, variceal bleeding,encephalopathy, depression, malaise, renal disease, arthritis, portalvein thrombosis and/or budd-chiari. Thus, in one aspect, the methodsdescribed herein involve oral administration of a testosterone ester(e.g., testosterone undecanoate, testosterone tridecanoate, or acombination thereof) formulated with vitamin E, a vitamin E prodrug, ora vitamin E derivative. In a preferred aspect, the Vitamin E compound isd-alpha-tocopherol or d-alpha tocopherol acetate. In another preferredaspect, the amount of d-alpha-tocopherol (or it's acetate) administeredper day is from about 100 IU to about 2000 IU, 200 IU to about 1600 IUper day, about 400 IU to about 1000 IU per day or about 600 IU to 900 IUper day. These amounts can be co-formulated with the testosterone estersor administered separately. The exemplary formulations described hereincan be adapted accordingly to use d-alpha-tocopherol (or e.g., a prodrugthereof (d-alpha-tocopheryl acetate)), tocotrienol and other relatedVitamin E related compounds. Thus, in certain aspects of this embodimenta method of treating a subject in need of treatment is provided, saidmethod comprising identifying a subject in need of treatment (e.g., hasa liver disease or condition) and orally administering a pharmaceuticalcomposition having a testosterone ester (e.g., testosterone undecanoateor testosterone tridecanoate) to said subject in combination with one ormore immunosuppressive agents. In one aspect, the subject in need oftreatment has one or more biomarkers (or clinical characteristics)indicating a need for combination treatment. In one aspect, the one ormore biomarkers are outside the normal range. In one aspect, the one ormore biomarkers are above the normal range but below 2 times the upperlimit of the normal range. In one aspect of this method, the subject hastestosterone deficiency. In one aspect, said subject in need oftreatment has testosterone deficiency with serum testosterone levels ofless than 350 ng/dL, 300 ng/dL, 250 ng/dL, 200 ng/dL, 150 ng/dL or 100ng/dL. In one aspect, the one or more biomarkers are above the normalrange but between 2-3 times the upper limit of the normal range or more.In one aspect, the one or more biomarkers are above the normal range butbelow 2 times the upper limit of the normal range. In one aspect of thismethod, oral administration of the testosterone ester improves liverdisease or reduces the risk of liver disease while not substantiallyincreasing serum levels of or decreases serum levels oflipoprotein-associated phospholipase A2. In one aspect, said methodincreases said subject's serum testosterone levels over their baseline.In another aspect said method increases said subject's serumtestosterone levels into the normal range. In one aspect, said methodcomprises oral administration of 200 mg to 750 mg of testosteroneundecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of 300 mg to 600 mg of testosteroneundecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of 450 mg of testosterone undecanoate perday to a male subject. In one aspect, said method comprises oraladministration of about 400 mg to 2000 mg of testosterone tridecanoateper day to a male subject. In one aspect, said method comprises oraladministration of about 600 mg to 1800 mg of testosterone tridecanoateper day to a male subject. In one aspect, said method comprises oraladministration of about 500 mg, 750 mg, 1000 mg, or 1250 mg oftestosterone tridecanoate per day to a male subject. These dose rangesare typically those for male subjects whereas the female dose rangecorresponds to about 1/10th- 1/15th of these values. In one aspect thesubject is from 18-25 years old, 26-35 years old, 36-45 years old, 45-55years old, 56-65 years old or older than 65 years old. In one aspect,the biomarker is one or more chosen from ALP, ALT, AST, GGT,triglycerides, LDL, cholesterol, liver biopsy, inflammation biomarkers,non-HDL cholesterol, hematocrit, hemoglobin, lipoprotein phospholipaseA2, bilirubin, albumin, SHBG, any specific biomarkers disclosed in theTables of Example 1, imaging biomarkers, liver histology biomarkers,biomarkers in the literature related to the disease and conditiondescribed herein, and liver damage biomarkers. In one aspect of thisembodiment, the subject has one or more of the following comorbidities:obesity, type 2 diabetes, dyslipidemia, cardiovascular disease, thyroiddysfunction, chronic kidney disease, liver disease, osteoporosis,hypogonadism, hypertension, sarcopenia, or cachexia.

In certain embodiments related to the treatment of liver disease, liverinjury, NAFLD, NASH or cirrhosis which occurs secondary to a livertransplant, including acute and chronic transplant rejection, thecompositions described hereincan be co-administered (e.g., according tothe methods described herein) to the transplant patient with aneffective amount at least one immunosuppressive agent chosen fromSandimmune (cyclosporine), Neoral (cyclosporine), Prograf (tacrolimus),prednisone, Imuran (azathioprine), Cellcept (mycophenolate mofetil),Zenapax (daclizumab), or Simulect (basiliximab). Thus, in certainaspects of this embodiment a method of treating a subject in need oftreatment is provided, said method comprising identifying a subject inneed of treatment (e.g., a subject that has had a liver transplant) andorally administering a pharmaceutical composition having a testosteroneester (e.g., testosterone undecanoate or testosterone tridecanoate) tosaid subject in combination with one or more immunosuppressive agents.In one aspect, the subject in need of treatment has one or morebiomarkers (or clinical characteristics) indicating a need forcombination treatment. In one aspect, the one or more biomarkers areoutside the normal range. In one aspect, the one or more biomarkers areabove the normal range but below 2 times the upper limit of the normalrange. In one aspect of this method, the subject has testosteronedeficiency. In one aspect, said subject in need of treatment hastestosterone deficiency with serum testosterone levels of less than 350ng/dL, 300 ng/dL, 250 ng/dL, 200 ng/dL, 150 ng/dL or 100 ng/dL. In oneaspect, the one or more biomarkers are above the normal range butbetween 2-3 times the upper limit of the normal range or more. In oneaspect, the one or more biomarkers are above the normal range but below2 times the upper limit of the normal range. In one aspect of thismethod, oral administration of the testosterone ester improves liverdisease or reduces the risk of liver disease while not substantiallyincreasing serum levels of or decreases serum levels oflipoprotein-associated phospholipase A2. In one aspect, said methodincreases said subject's serum testosterone levels over their baseline.In another aspect said method increases said subject's serumtestosterone levels into the normal range. In one aspect, said methodcomprises oral administration of 200 mg to 750 mg of testosteroneundecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of 300 mg to 600 mg of testosteroneundecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of 450 mg of testosterone undecanoate perday to a male subject. In one aspect, said method comprises oraladministration of about 400 mg to 2000 mg of testosterone tridecanoateper day to a male subject. In one aspect, said method comprises oraladministration of about 600 mg to 1800 mg of testosterone tridecanoateper day to a male subject. In one aspect, said method comprises oraladministration of about 500 mg, 750 mg, 1000 mg, or 1250 mg oftestosterone tridecanoate per day to a male subject. These dose rangesare typically those for male subjects whereas the female dose rangecorresponds to about 1/10th- 1/15th of these values. In one aspect thesubject is from 18-25 years old, 26-35 years old, 36-45 years old, 45-55years old, 56-65 years old or older than 65 years old. In one aspect,the biomarker is one or more chosen from ALP, ALT, AST, GGT,triglycerides, LDL, cholesterol, liver biopsy, inflammation biomarkers,non-HDL cholesterol, hematocrit, hemoglobin, lipoprotein phospholipaseA2, bilirubin, albumin, SHBG, any specific biomarkers disclosed in theTables of Example 1, imaging biomarkers, liver histology biomarkers,biomarkers in the literature related to the disease and conditiondescribed herein, and liver damage biomarkers. In one aspect of thisembodiment, the subject has one or more of the following comorbidities:obesity, type 2 diabetes, dyslipidemia, cardiovascular disease, thyroiddysfunction, chronic kidney disease, liver disease, osteoporosis,hypogonadism, hypertension, sarcopenia, or cachexia.

In other alternative embodiments, the compositions described herein canbe administered to a patient where applicable (in those conditions suchas NAFLD, NASH, etc. which occur as a consequence of metabolic syndromeand/or type II diabetes) in combination with an effective amount of oneor more agents which are used to treat type II diabetes or metabolicsyndrome including metformin, glibenclamide, gliclazide, rosiglitazone,pioglitazone, troglitazone, acarbose, miglitol, nateglinide,repaglinide, exenatide, sitagliptin, pramlintide and mixtures thereof.Thus, in certain aspects of this embodiment a method of treating asubject in need of treatment is provided, said method comprisingidentifying a subject in need of treatment (e.g., a subject that hasliver disease or is at risk of having liver disease) and orallyadministering a pharmaceutical composition having a testosterone ester(e.g., testosterone undecanoate or testosterone tridecanoate) to saidsubject in combination with an agent useful for treating type IIdiabetes or metabolic syndrome. In one aspect, the subject in need oftreatment has one or more biomarkers (or clinical characteristics)indicating a need for combination treatment. In one aspect, the one ormore biomarkers are outside the normal range. In one aspect, the one ormore biomarkers are above the normal range but below 2 times the upperlimit of the normal range. In one aspect of this method, the subject hastestosterone deficiency. In one aspect, said subject in need oftreatment has testosterone deficiency with serum testosterone levels ofless than 350 ng/dL, 300 ng/dL, 250 ng/dL, 200 ng/dL, 150 ng/dL or 100ng/dL. In one aspect, the one or more biomarkers are above the normalrange but between 2-3 times the upper limit of the normal range or more.In one aspect, the one or more biomarkers are above the normal range butbelow 2 times the upper limit of the normal range. In one aspect of thismethod, the subject has testosterone deficiency. In one aspect of thismethod, oral administration of the testosterone ester improves liverdisease or reduces the risk of liver disease while not substantiallyincreasing serum levels of or decreases serum levels oflipoprotein-associated phospholipase A2. In one aspect, said methodincreases said subject's serum testosterone levels over their baseline.In another aspect said method increases said subject's serumtestosterone levels into the normal range. In one aspect, said methodcomprise oral administration of 200 mg to 750 mg of testosteroneundecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of 300 mg to 600 mg of testosteroneundecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of 450 mg of testosterone undecanoate perday to a male subject. In one aspect, said method comprises oraladministration of about 400 mg to 2000 mg of testosterone tridecanoateper day to a male subject. In one aspect, said method comprises oraladministration of about 600 mg to 1800 mg of testosterone tridecanoateper day to a male subject. In one aspect, said method comprises oraladministration of about 500 mg, 750 mg, 1000 mg, or 1250 mg oftestosterone tridecanoate per day to a male subject. These dose rangesare typically those for male subjects whereas the female dose rangecorresponds to about 1/10th- 1/15th of these values. In one aspect thesubject is from 18-25 years old, 26-35 years old, 36-45 years old, 46-55years old, 56-65 years old or older than 65 years old. In one aspect,the biomarker is one or more chosen from ALP, ALT, AST, GGT,triglycerides, LDL, cholesterol, liver biopsy, inflammation biomarkers,non-HDL cholesterol, hematocrit, hemoglobin, lipoprotein phospholipaseA2, bilirubin, albumin, SHBG, any specific biomarkers disclosed in theTables of Example 1, imaging biomarkers, liver histology biomarkers,biomarkers in the literature related to the disease and conditiondescribed herein, and liver damage biomarkers. In one aspect of thisembodiment, the subject has one or more of the following comorbidities:obesity, dyslipidemia, cardiovascular disease, thyroid dysfunction,chronic kidney disease, liver disease, osteoporosis, hypogonadism,hypertension, sarcopenia, or cachexia.

Certain embodiments relate to the treatment of hepatitis (alcoholic andnon-alcoholic), which occurs as a consequence of infections (viral andnon-viral), drugs, ischemia, toxins, pregnancy, alcohol, toxins,autoimmune conditions (systemic lupus erythematosus) and metabolicconditions, including Wilson's disease, hemochromatosis and alpha oneantitrypsin deficiency. Hepatitis which may be treated according to thepresent invention includes hepatitis which occurs as a consequence ofinfectious disease, especially including a viral infection such as ahepatitis A, B, C, D or E viral infection, or hepatitis which occurs asa consequence of a cytomegalovirus, Epstein-Barr, yellow fever, mumpsvirus, rubella virus, herpes simplex virus, or adenovirus infection or anon-viral selection including an infection from toxoplasma, leptospira,Q fever or Rocky Mountain Spotted Fever. In this embodiment, an androgenreceptor agonist (e.g., testosterone undecanoate, testosteronetridecanoate, or a combination thereof) is administered in effectiveamounts to a patient with a viral hepatitis infection in order toinhibit, treat or reduce the likelihood of liver injury which occurs asa consequence of that viral or non-viral infection. Compositionsdescribed herein can be administered alone or in combination with aneffective amount of an anti-hepatitis infectious agent, such as ananti-viral agent, including Hepsera (adefovir dipivoxil), lamivudine,entecavir, telbivudine, tenofovir, emtricitabine, clevudine,valtoricitabine, amdoxovir, pradefovir, racivir, BAM 205, nitazoxanide,UT 231-B, Bay 41-4109, EHT899, zadaxin (thymosin alpha-1) and mixturesthereof for hepatitis B infections and NM 283, VX-950 (telaprevir), SCH50304, TMC435, VX-500, BX-813, SCH503034, R1626, ITMN-191 (R7227),R7128, PF-868554, TT033, CGH-759, GI 5005, MK-7009, SIRNA-034, MK-0608,A-837093, GS 9190, ACH-1095, GSK625433, TG4040 (MVA-HCV), A-831, F351,NS5A, NS4B, ANA598, A-689, GNI-104, IDX102, ADX184, GL59728, GL60667,PSI-7851, TLR9 Agonist, PHX1766, SP-30 and mixtures thereof forhepatitis C infections. In some embodiments, additional pharmaceuticalcompositions especially useful for treating hepatitis from viralinfections, in particular, hepatitis b or hepatitis C infectionscomprise an effective amount of one or more androgen receptor agonists(e.g., testosterone undecanoate or testosterone tridecanoate) asdisclosed herein in combination with at least one agent selected fromthe group consisting of hepsera (adefovir dipivoxil), lamivudine,entecavir, telbivudine, tenofovir, emtricitabine, clevudine,valtoricitabine, amdoxovir, pradefovir, racivir, BAM 205, nitazoxanide,UT 231-B, Bay 41-4109, EHT899, zadaxin (thymosin alpha-1) and mixturesthereof for hepatitis B infections and NM 283, VX-950 (telaprevir), SCH50304, TMC435, VX-500, BX-813, SCH503034 (boceprevir), R1626, ITMN-191(R7227), R7128, PF-868554, TT033, CGH-759, GI 5005, MK-7009, SIRNA-034,MK-0608, A-837093, GS 9190, ACH-1095, GSK625433, TG4040 (MVA-HCV),A-831, F351, NS5A, NS4B, ANA598, A-689, GNI-104, IDX102, ADX184,GL59728, GL60667, PSI-7851, TLR9 Agonist, PHX1766, SP-30 and mixturesthereof, in combination with a pharmaceutically acceptable carrier,additive or excipient.

Biomarkers

Any appropriate biomarker can be used in the methods and compositionsdescribed herein (including imaging analysis, histology, genetic,microRNA and the such). Specific biomarkers are described herein in themethod embodiments and Examples. Additional biomarkers, including somethat are described herein elsewhere, are illustrated below.

In one embodiment, the methods and compositions described herein, areuseful for treating a subject in need of treatment e.g., having NASH orsuspected of having NASH or having fatty liver disease or having liverdisease. Thus, the methods and compositions described herein can be usedto treat NASH (or suspected of having NASH or having fatty liver diseaseor having liver disease) of any grade or type. In one aspect, themethods and compositions as disclosed herein, reduce liver fat (or e.g.,steatosis) or reduce the rate of increase in liver fat (or steatosis).In one aspect, the methods and compositions can reduce liver fat bygreater than 5%, 10%, 15%, 20%, 25% or 30% in at least 1, 5, 10, 20, 30,40, or 50% of subjects treated. In one aspect, the biomarker (liver fat)is determined as a % mean relative reduction in liver fat reduction withMRI-PDFF (Magnetic Resonance Imaging-Derived Proton Density FatFraction). In one aspect, the methods and compositions reduce livertriglyceride concentration or decrease the rate of increase livertriglyceride concentration. In one aspect, the biomarker (livertriglyceride concentration) is measured by NMRS (magnetic resonancespectroscopy). In one aspect, the method and composition can improve orameliorate diffuse liver disease due to liver fat or iron deposition by5%, 10%, 15%, 20% or 25% or more. In one aspect, non-invasive magneticresonance imaging (MRI-PDFF) is sued for the evaluation of liver fat oriron deposition. In one aspect, the methods and compositions disclosedherein, ameliorates fatty infiltration (e.g., reduces fatty infiltrationor reduces the rate of increase of fatty infiltration). In one aspect,abdominal ultrasound is used to determine fatty infiltration. In oneaspect, CT (computed tomography) is used to assess the liver biomarker.In one aspect, the methods and compositions described herein improveliver stiffness (LS)/fibrosis. In one aspect, improved liverstiffness/fibrosis is at least a 5, 10, 15, 20 or 25% reduction in MRE(Magnetic Resonance Elastography)-stiffness. In one aspect, ultrasoundbased elastography is used for the assessment of liver tissue stiffnessin fibrosis. In one aspect, transient elastography (TE) (e.g.,Fibroscan®, Echosens, Paris) is used (ultrasound-based elastography) todetermine liver stiffness. In one aspect, pSWE (Elastography pointquantification, ELASTPQ™, Phillips) or ARFI imaging (Virtual touchtissue Quantification™, Siemens) is (ultrasound-based elastographytechniques) used to assess liver stiffness. In one aspect, liverstiffness is monitored via Real Time TE (RTE) which is a qualitativeassessment of liver stiffness. Magnetic resonance elastography (MRE) candetermine liver stiffness by analysis of mechanical waves propagatingthrough the liver. In one aspect, the methods and compositions disclosedherein reduce liver stiffness by 5, 10, 20, 30, 40, 50, 60 or 75% ormore. In one aspect, the methods and compositions disclosed hereinreduce the rate of increase of liver stiffness by 5, 10, 20, 30, 40, 50,60 or 75% or more. In one aspect, the method and compositions disclosedherein improve on liver fibrosis as measured by non-invasiveLiverMultiscan. In one aspect, the method and compositions reducehepatic steatosis as monitored by imaging studies along with decreasingin ALT, CK18, or both. In one aspect, the methods and compositionsdescribed herein improve or ameliorate liver fibrosis as assessed byhistology and reduces risk of progression to cirrhosis. In one aspect,the methods and compositions described herein improve by at least 1 or 2points (e.g., decrease) the NAFLD activity score (NAS). In one aspect,the methods and compositions described herein improve at least a pointreduction in either lobular inflammation or hepatocellular ballooning.In one aspect, the methods and compositions improve or resolve NASH onoverall histopathological interpretation by an experienced pathologist(e.g., target score of 0 on ballooning and 0 or 1 for inflammation, butno greater than 1) and no worsening of fibrosis (e.g., no one stageincrease in on fibrosis score). In one aspect, the methods andcompositions described herein reverse NASH (e.g., change from NAS scorefrom 5 to 3) with no evidence of progression to advanced fibrosis (e.g.,stage 3 or 4). In one aspect, the methods and compositions describedherein improve fibrosis (e.g., lessen) without worsening of NAS or noprogression of steatohepatitis (or reduce progression ofsteatohepatitis). In one aspect, the methods and compositions describedherein do not increase NAFLD activity as assessed by NAS and lessen orreverse fibrosis. In one aspect, the methods and compositions describedherein when used in a population of patients, at least 10%, 20%, 30% 40%or 50% or more achieve a ≥1-Stage Improvement in Fibrosis According tothe NASH Clinical Research Network (CRN) Classification WithoutWorsening of NASH. In one aspect, the methods and compositions describedherein prevent the development of cirrhosis or lessen the likelihood ofprogression to cirrhosis. In one aspect, the methods and compositionsdescribed herein slowing histological progression to cirrhosis. In oneaspect, the methods and compositions described herein improve event freesurvival (e.g., as assessed by all-cause mortality, new decompensationevents, MELD score progression). In one aspect, the methods andcompositions described herein decrease in all-cause mortality. In oneaspect, the methods and compositions described herein decrease in liverspecific mortality. In one aspect, the methods and compositionsdescribed herein decrease liver transplantation rates. In one aspect,the methods and compositions described herein increase 12 month survivalrates. In one aspect, the methods and compositions described hereinincrease event free survival (EFS) at week 52 as Assessed by Time to theFirst Clinical Event. In one aspect, the methods and compositionsdescribed herein decrease events/rate of events of decompensation incompensated patients. In one aspect, the methods and compositionsdescribed herein decrease rate of ascites events or ascites grade. Inone aspect, the methods and compositions described herein decrease rateof HE or progress in HE (e.g., as assessed by MRI). In one aspect, themethods and compositions described herein decrease in hospitaladmissions or hospital admission rates. In one aspect, the methods andcompositions described herein decrease unscheduled clinic or ER visit.In one aspect, the methods and compositions described herein decreasethe number of tests performed. In one aspect, the methods andcompositions described herein decrease lost work days. In one aspect,the methods and compositions described herein decrease infection ratesor number of events. In one aspect, the methods and compositionsdescribed herein improve the Child-Pugh-Turcotte Score. In one aspect,the methods and compositions described herein lower Progression from Ato B In one aspect, the methods and compositions described herein do notworsen CPT. In one aspect, the methods and compositions described hereinimprove CPT score by at least 1 or 2 points. In one aspect, the methodsand compositions described herein improve MELD score. In one aspect, themethods and compositions described herein lessen responder progressionto higher MELD score. In one aspect, the methods and compositionsdescribed herein do not worsen MELD score. In one aspect, the methodsand compositions described herein improve MELD score by at least one ortwo points. In one aspect, the methods and compositions described hereinlower % of subjects achieving transplantation qualifying MELD score of14. In one aspect, the methods and compositions described hereinincrease in MELD score from <12 to 15 or higher. In one aspect, themethods and compositions described herein improve the hepatic venouspressure gradient (HVPG). In one aspect, the methods and compositionsdescribed herein reduce of proportion of subjects that progress toHVPG >10 mm. In one aspect, the methods and compositions describedherein lower HVPG <10 mm. In one aspect, the methods and compositionsdescribed herein reduce HVPG by 5, 10, 15, 20, 25 or 30% or more. In oneaspect, the methods and compositions described herein improve bodycomposition. In one aspect, the methods and compositions describedherein improve bone density (e.g., one or more of femoral, lumbar, neck,and total bone mass. In one aspect, the methods and compositionsdescribed herein improve anemia. In one aspect, the methods andcompositions described herein improve gynecomastia (e.g., lessen). Inone embodiment, a method of reducing progression or the risk ofprogression of NASH to cirrhosis a subject having or suspected of havingNASH is provided said method comprising oral administration of apharmaceutical composition having a testosterone ester (e.g.,testosterone undecanoate or testosterone tridecanoate) to said subject.In one aspect, the subject is in need of treatment e.g., has NASH or isat risk of having NASH progressing to cirrhosis. In one aspect, thesubject in need of treatment has one or more biomarkers (or clinicalcharacteristics) indicating an increased risk of NASH progressing tocirrhosis. In one aspect, the one or more biomarkers are outside thenormal range. In one aspect, the one or more biomarkers are above thenormal range but below 2 times the upper limit of the normal range. Inone aspect of this method, the subject has testosterone deficiency. Inone aspect, said subject in need of treatment has testosteronedeficiency with serum testosterone levels of less than 350 ng/dL, 300ng/dL, 250 ng/dL, 200 ng/dL, 150 ng/dL or 100 ng/dL. In one aspect, theone or more biomarkers are above the normal range but between 2-3 timesthe upper limit of the normal range or more. In one aspect, the one ormore biomarkers are above the normal range but below 2 times the upperlimit of the normal range. In one aspect of this method, the subject hastestosterone deficiency. In one aspect of this method, oraladministration of the testosterone ester reduces the progression of NASHto cirrhosis while not substantially increasing serum levels of ordecreases serum levels of lipoprotein-associated phospholipase A2. Inone aspect, said method increases said subject's serum testosteronelevels over their baseline. In another aspect said method increases saidsubject's serum testosterone levels into the normal range. In oneaspect, said method comprises oral administration of 200 mg to 750 mg oftestosterone undecanoate per day to a male subject. In one aspect, saidmethod comprises oral administration of 300 mg to 600 mg of testosteroneundecanoate per day to a male subject. In one aspect, said methodcomprises oral administration of 450 mg of testosterone undecanoate perday to a male subject. In one aspect, said method comprises oraladministration of about 400 mg to 2000 mg of testosterone tridecanoateper day to a male subject. In one aspect, said method comprises oraladministration of about 600 mg to 1800 mg of testosterone tridecanoateper day to a male subject. In one aspect, said method comprises oraladministration of about 500 mg, 750 mg, 1000 mg, or 1250 mg oftestosterone tridecanoate per day to a male subject. These dose rangesare typically those for male subjects whereas the female dose rangecorresponds to about 1/10th- 1/15th of these values. In one aspect thesubject is from 18-25 years old, 26-35 years old, 36-45 years old, 46-55years old, 56-65 years old or older than 65 years old. In one aspect,the biomarker is one or more chosen from ALP, ALT, AST, GGT,triglycerides, LDL, cholesterol, liver biopsy, inflammation biomarkers,non-HDL cholesterol, hematocrit, hemoglobin, lipoprotein phospholipaseA2, bilirubin, albumin, SHBG, any specific biomarkers disclosed in theTables of Example 1, imaging biomarkers, liver histology biomarkers,biomarkers in the literature related to the disease and conditiondescribed herein, and liver damage biomarkers. In one aspect of thisembodiment, the subject has one or more of the following comorbidities:obesity, type 2 diabetes, dyslipidemia, cardiovascular disease, thyroiddysfunction, chronic kidney disease, liver disease, osteoporosis,hypogonadism, hypertension, sarcopenia, or cachexia.

In one aspect, the methods and compositions disclosed herein improve orameliorate, changes in body composition, muscle mass, appendicular leanmass, total lean mass, fat mass, high VAT (visceral adipose fat), waistcircumference, weight gain, change in BMI, mobility/frailty: (e.g.,timed up and go-TUG (mobility) score, hand grip strength, liver frailtyindex as measured by score in functional assessments of grip strength(kg), balance (seconds), and chair stands (seconds)), PROs: functionalstatus of patient-COA-symptoms only known to patients, QOL (quality oflife) assessed by the CLDQ, perceived HRQoL score, depression, mobility,sexual dysfunction, and FIS fatigue questionnaire, in a subject in needof treatment (e.g., as described in the method embodiments describedherein and specifically subjects having cirrhosis, NASH, NAFLD,steatohepatitis, liver disease). In one embodiment, a method of reducingprogression or the risk of progression of NASH to cirrhosis a subjecthaving or suspected of having NASH is provided said method comprisingoral administration of a pharmaceutical composition having atestosterone ester (e.g., testosterone undecanoate or testosteronetridecanoate) to said subject. In one aspect, the subject is in need oftreatment e.g., has NASH or is at risk of having NASH progressing tocirrhosis. In one aspect, the subject in need of treatment has one ormore biomarkers (or clinical characteristics) indicating an increasedrisk of NASH progressing to cirrhosis. In one aspect, the one or morebiomarkers are outside the normal range. In one aspect, the one or morebiomarkers are above the normal range but below 2 times the upper limitof the normal range. In one aspect of this method, the subject hastestosterone deficiency. In one aspect, said subject in need oftreatment has testosterone deficiency with serum testosterone levels ofless than 350 ng/dL, 300 ng/dL, 250 ng/dL, 200 ng/dL, 150 ng/dL or 100ng/dL. In one aspect, the one or more biomarkers are above the normalrange but between 2-3 times the upper limit of the normal range or more.In one aspect, the one or more biomarkers are above the normal range butbelow 2 times the upper limit of the normal range. In one aspect of thismethod, the subject has testosterone deficiency. In one aspect of thismethod, oral administration of the testosterone ester reduces theprogression of NASH to cirrhosis while not substantially increasingserum levels of or decreases serum levels of lipoprotein-associatedphospholipase A2. In one aspect, said method increases said subject'sserum testosterone levels over their baseline. In another aspect saidmethod increases said subject's serum testosterone levels into thenormal range. In one aspect, said method comprises oral administrationof 200 mg to 750 mg of testosterone undecanoate per day to a malesubject. In one aspect, said method comprises oral administration of 300mg to 600 mg of testosterone undecanoate per day to a male subject. Inone aspect, said method comprises oral administration of 450 mg oftestosterone undecanoate per day to a male subject. In one aspect, saidmethod comprises oral administration of about 400 mg to 2000 mg oftestosterone tridecanoate per day to a male subject. In one aspect, saidmethod comprises oral administration of about 600 mg to 1800 mg oftestosterone tridecanoate per day to a male subject. In one aspect, saidmethod comprises oral administration of about 500 mg, 750 mg, 1000 mg,or 1250 mg of testosterone tridecanoate per day to a male subject. Thesedose ranges are typically those for male subjects whereas the femaledose range corresponds to about 1/10th- 1/15th of these values. In oneaspect the subject is from 18-25 years old, 26-35 years old, 36-45 yearsold, 46-55 years old, 56-65 years old or older than 65 years old. In oneaspect, the biomarker is one or more chosen from ALP, ALT, AST, GGT,triglycerides, LDL, cholesterol, liver biopsy, inflammation biomarkers,non-HDL cholesterol, hematocrit, hemoglobin, lipoprotein phospholipaseA2, bilirubin, albumin, SHBG, any specific biomarkers disclosed in theTables of Example 1, imaging biomarkers, liver histology biomarkers,biomarkers in the literature related to the disease and conditiondescribed herein, and liver damage biomarkers. In one aspect of thisembodiment, the subject has one or more of the following comorbidities:obesity, type 2 diabetes, dyslipidemia, cardiovascular disease, thyroiddysfunction, chronic kidney disease, liver disease, osteoporosis,hypogonadism, hypertension, sarcopenia, or cachexia.

In one aspect, the methods and compositions described herein areutilized in conjunction with one, two or three or more serum biomarkers.

In one aspect, the methods and compositions described herein areutilized in conjunction with one, two or three or more lipogenesis/lipidtransporters biomarkers.

In one aspect, the methods and compositions described herein areutilized in conjunction with one, two or three or more lipogenesis/lipidtransporters biomarkers chosen from acetyl-coA carboxylase (ACC), fattyacid transport protein-5 (FATP-5) or the fatty acid transporter CD36,liver-fatty acid binding protein (FABP), Ceramides, 3-nitrotyrosine(oxidative stress marker), HNE (4-hydroxy-2-noneal, a marker of lipidperoxidation), 8-hydroxydeoxyguanosine (a marker of oxidative DNAdamage), Glutamate dehydrogenase (mitochondrial marker enzyme), Glucose6-phosphatase (microsomal enzyme marker), LD or LDH (Lactatedehydrogenase), and resitsin.

In one aspect, the methods and compositions described herein areutilized in conjunction with one, two or three or more lipo-Apoptosisbiomarkers e.g., CK-18 (cytokeratin 18) Cathepsin B, caspase cleavedCK18, flCK, caspase 3/7, platelet count, full blood cell count (e.g.,thrombocytopenia, α1-antitrypsin, ferritin, and adipokines (e.g.,adiponectin and leptin).

In one aspect, the methods and compositions described herein areutilized in conjunction with one, two or three or more metalloproteinasebiomarkers e.g., (MMPs)-MMPs 2, MMP-3, and MMP-9.

In one aspect, the methods and compositions described herein areutilized in conjunction with transforming growth factor (TGF)-β1 as abiomarker.

In one aspect, the methods and compositions described herein areutilized in conjunction with one or more tissue inhibitors ofmetalloproteinases (TIMPs) as biomarkers e.g., TIMP-1, TIMP-2,Microfibril-associated protein 4 (MFAP4).

In one aspect, the methods and compositions described herein areutilized in conjunction with hyaluronic acid (HA) N Glycans profiles asbiomarkers.

In one aspect, the methods and compositions described herein areutilized in conjunction with one or more of the following biomarkers:Laminin, Procollagen type III amino-terminal peptide (PIIINP),Chitinase-3-like protein 1 (CHI3L1 or YKL-40), CTGF (connective tissuegrowth factor), and Collagen type IV-S or VI.

In one aspect, the methods and compositions described herein areutilized in conjunction with pro-inflammation and pro-fibrotic mediatorsas biomarkers.

In one aspect, the methods and compositions described herein areutilized in conjunction with one, two or three or more of hs-CRP orcytokine biomarkers. In one aspect, the methods and compositionsdescribed herein are utilized in conjunction with one, two or three ormore biomarkers chosen from IL-1, IL-1 beta, NF-KappaB,MCP-1(CCL2-Chemokine) IL-6, IL-8, RBP-4, soluble CD14, TNF-alpha, MCP-1,leptin, visfatin, adiponectin, fibrinogen, fibrinonectin, collagens(I-III), undulin, elastin, proteoglycans, PICP (procollagen type 1carboxy terminal peptide), ICAM, VCAM (adhesion molecules), and JNK(protein kinase).

In one aspect, the methods and compositions described herein areutilized in conjunction with one, two or three or more biomarkers thatare liver enzymes. In one aspect, the methods and compositions describedherein are utilized in conjunction with one, two or three or more ofalanine amino transferase (ALT), aspartate amino transferase (AST),alkaline phosphatase (ALP), and gamma glutamyl transferase (GGT).

In one aspect, the methods and compositions described herein areutilized in conjunction with one, two or three or more biomarkers ofsynthetic function. In one aspect, the methods and compositionsdescribed herein are utilized in conjunction with one, two or three ormore biomarkers of synthetic function chosen from prothrombin time(PT/INR), bilirubin, haptoglobin, hemoglobin, albumin, ApolipoproteinA1, α2-macroglobulin, ceruloplasmin, transferrin and hepcidin, sodiumserum alpha protein, circulating ammonia, and creatinine.

In one aspect, the methods and compositions described herein areutilized in conjunction with one, two or three or more hormone orendocrine biomarkers. In one aspect, the methods and compositionsdescribed herein are utilized in conjunction with one, two or three ormore hormone or endocrine biomarkers chosen from Prolactin, LH, FSH, E,TT, freeT, DHT, SHBG, oestrone, thyroid panel, and cortisol.

In one aspect, the methods and compositions described herein areutilized in conjunction with one, two or three or more hypertensionrelated biomarkers.

In one aspect, the methods and compositions described herein areutilized in conjunction with one, two or three or more diabetes relatedbiomarkers. In one aspect, the methods and compositions described hereinare utilized in conjunction with one, two or three or more diabetesrelated biomarkers chosen from HB1AC, Impaired Fasting glucose, fastinginsulin, and HOMA-IR (Homeostasis Model Assessment-insulin resistance).

In one aspect, the methods and compositions described herein areutilized in conjunction with one, two or three or more anemia relatedbiomarkers. In one aspect, the methods and compositions described hereinare utilized in conjunction with one, two or three or more anemiarelated biomarkers chosen from hemoglobin levels, hematocrit levels,complete blood count (CBC), and MCV (e.g., a measure of the average sizeof red blood cells).

In one aspect, the methods and compositions described herein areutilized in conjunction with one, two or three or more dyslipidemiarelated biomarkers. In one aspect, the methods and compositionsdescribed herein are utilized in conjunction with one, two or three ormore dyslipidemia related biomarkers chosen from HDL, LDL, totalcholesterol, triglycerides, non HDL cholesterol, VLDL, saturated freefatty acid, unsaturated free fatty acid, total free fatty acid, ApoB,and apolipoprotein A1.

In one aspect, the methods and compositions described herein areutilized in conjunction with one, two or three or more sarcopeniarelated biomarkers. In one aspect, the methods and compositionsdescribed herein are utilized in conjunction with one, two or three ormore sarcopenia related biomarkers chosen from decrease in fat massrelative to fat free mass (includes muscle mass), DEXA scan for bonemineral, fat, bone-mineral-fat-free mass, fat-free skeletal muscle masse.g., obtained with an imaging technique (such as computerizedtomography (CT) and magnetic resonance imaging (MRI)), bioimpedanceanalysis (BIA) for muscle mass.

In one aspect, the methods and compositions described herein areutilized in conjunction with one, two or three of creatinine,3-methylhistidine, and urinary creatinine excretion.

In one aspect, the methods and compositions described herein areutilized in conjunction with one, two or three or more metabolicsyndrome related biomarkers e.g., sBP >130, hyper glycemia-fastingglucose >100, waist circumference >40 in men, TG >150, HDL <40

In one aspect, the methods and compositions described herein areutilized in conjunction with one, two or three or more combinationbiomarkers of liver fibrosis. In one aspect, the methods andcompositions described herein are utilized in conjunction with one, twoor three or more combination biomarkers of liver fibrosis chosen fromAST/ALT ratio, BARD related (e.g., BMI, AST, ALT, and DiabetesMellitus), and e.g., combinations of FIB-4, Platelet count, AST, ALT,and age.

Other biomarkers for use in the methods include, but are not limited to:

-   Fibrometer test—Platelet count, prothrombin index, AST,    α2-macro-globulin, hyaluronic acid, urea, age-   Fibrometer A—Prothrombin index, α2 macroglobulin, hyaluronic acid,    age-   Fibrotest (FT)—Haptoglobin, α2-macro-globulin, apolipoprotein A1.    GGT, bilirubin, age, gender-   NAFLD Fibrosis Score (NFS)—Age, BMI, platelets, albumin, AST/ALT,    IFG/diabetes-   Fibrospect-II—Hyaluronic acid, TIMP-1, α2-macroglobulin-   PGA-index—Prothrombin time, GGT, apolipoprotein A1-   PGAA-index—Prothrombin time, GGT, apolipoprotein A1,    α2-macroglobulin-   Pohl score—AST/ALT-ratio, platelet count-   ELF score—Hyaluronic acid, TIMP-1, age, MMP-3-   SHASTA—HA, AST, albumin-   Fibrosis probability-index, FPI— Age, AST, cholesterol, insulin    resistance (HOMA), past alcohol intake-   APRI score—AST, platelet count-   alpha2-macroglobulin, age, gamma glutamyl transpeptidase, and    hyaluronic acid.

Other Methods

A method of diagnosing NAFLD in a subject is provided herein said methodcomprising: determining the subjects serum testosterone level,determining the subjects BMI, or both, wherein a subject having lowtestosterones levels and a BMI greater than or equal to 30, or thesubject is obese, is diagnosed with NAFLD. According to this method, asubject diagnosed with NAFLD is furthered assessed by analyzing one ormore biomarkers or performing imaging studies to confirm diagnosis andstage as well as determine treatment. For example, a subject diagnosedwith liver is further assessed by MRI-PDFF or MRE, or one or more serumor NAS biomarkers are assessed. In one aspect, the biomarker is one ormore chosen from ALP, ALT, AST, GGT, TRIGLYCERIDES, LDL, Cholesterol,Liver Biopsy, inflammation biomarkers, non-HDL cholesterol, hematocrit,hemoglobin, lipoprotein phospholipase A2, bilirubin, albumin, SHBG,imaging biomarkers, liver histology biomarkers, biomarkers in theliterature related to the disease and condition described herein, andliver damage biomarkers.

In one embodiment, the subject diagnosed with the method describedherein (in those conditions such as NAFLD, NASH, etc. or which occur asa consequence of metabolic syndrome and/or type II diabetes) can betreated for NAFLD or NASH with of one or more agents which are used totreat type II diabetes or metabolic syndrome including metformin,glibenclamide, gliclazide, rosiglitazone, pioglitazone, troglitazone,acarbose, miglitol, nateglinide, repaglinide, exenatide, sitagliptin,pramlintide and mixtures thereof.

In one embodiment, the subject diagnosed (e.g., hypogonadal, obese,having fatty liver, having live fat greater than 8%, MRE, NAFLD, NASH,one or more serum biomarkers described herein, etc.) with the methoddescribed herein can be treated for NAFLD or NASH with of one or morepharmaceutical agents that inhibits c-Jun N-terminal kinase, p38mitogen-activated protein kinase, or both.

In one embodiment, the subject diagnosed (e.g., hypogonadal, obese,having fatty liver, having live fat greater than 8%, MRE, NAFLD, NASH,one or more serum biomarkers described herein, etc.) with the methoddescribed herein can be treated for NAFLD or NASH with of one or morepharmaceutical agents that inhibits ASK1 kinase. One example of such anagent is selonsertib.

In one embodiment, the subject diagnosed (e.g., hypogonadal, obese,having fatty liver, having live fat greater than 8%, MRE, NAFLD, NASH,one or more serum biomarkers described herein, etc.) with the methoddescribed herein can be treated for NAFLD or NASH with of one or morepharmaceutical agents is an agonist of farnesoid X receptor. One exampleof such an agent is obeticholic acid.

In one embodiment, the subject diagnosed (e.g., hypogonadal, obese,having fatty liver, having live fat greater than 8%, MRE, NAFLD, NASH,one or more serum biomarkers described herein, etc.) with the methoddescribed herein can be treated for NAFLD or NASH with of one or morepharmaceutical agents is an inhibitor of the peroxisomeproliferator-activated receptor alpha, delta, or both. One example ofsuch an agent is elafibrinor.

In one embodiment, the subject diagnosed (e.g., hypogonadal, obese,having fatty liver, having live fat greater than 8%, MRE, NAFLD, NASH,one or more serum biomarkers described herein, etc.) with the methoddescribed herein can be treated for NAFLD or NASH with of one or morepharmaceutical agents is an antagonist of C—C chemokine receptor types2, 5, or both. One example of such an agent is cenicriviroc.

In one embodiment, the subject diagnosed (e.g., hypogonadal, obese,having fatty liver, having live fat greater than 8%, MRE, NAFLD, NASH,one or more serum biomarkers described herein, etc.) with the methoddescribed herein can be treated for NAFLD or NASH with of one or morepharmaceutical agents that is chosen from butanoic acid, CER209,evogliptin, DUR928, MK-4074, OPRX-106, PF06865571, PF06882961,PXS-5382A, RG-125, RYI-018, seladelpar, SGM-1019, TVB-2640, or acombination thereof.

In one embodiment, the subject diagnosed (e.g., hypogonadal, obese,having fatty liver, having live fat greater than 8%, MRE, NAFLD, NASH,one or more serum biomarkers described herein, etc.) with the methoddescribed herein can be treated for NAFLD or NASH with of one or morepharmaceutical agents that is chosen from aramchol, ARX618, BI 1467335,DS102, EDP-305, Emricasan, gemcabene, GR-MD-02, GRI-0621, GS-0976,GS-9674, IMM-124E, IONIS-DGAT2Rx, IVA-337, Lipaglyn, LJN452, LMB763,MGL-3196, MN-001, MSDC-0602K, NC101, NGM282, NS-0200, Ozempic,PF-05221304, PF-06835919, remogliflozin etabonate, SHP626, TVB-2640,VK2809, or a combination thereof.

In one embodiment, the subject diagnosed (e.g., hypogonadal, obese,having fatty liver, having live fat greater than 8%, MRE, NAFLD, NASH,one or more serum biomarkers described herein, etc.) with the methoddescribed herein can be treated for NAFLD or NASH with of one or morepharmaceutical agents that is chosen from cenicriviroc, elafibranor,ocaliva (obeticholic acid), selonsertib, or a combination thereof.

In one embodiment, the subject diagnosed (e.g., hypogonadal, obese,having fatty liver, having live fat greater than 8%, MRE, NAFLD, NASH,one or more serum biomarkers described herein, etc.) with the methoddescribed herein can be treated for NAFLD or NASH with of one or morepharmaceutical agents is an androgen receptor agonist. One example ofsuch an agent is testosterone or a testosterone ester (and in apreferred aspect testosterone or testosterone ester formulated for anddelivered orally).

In some embodiments of the methods disclosed herein, the subjectdiagnosed according to the instant disclosure is administered oraltestosterone ester therapy. In one aspect, the oral testosterone therapyis administered with one or more additional therapeutic agents (notnecessarily at the same time or frequency as the oral testosterone estertherapy or androgen receptor agonist therapy).

In some embodiments the one or more additional therapeutic agent is astatin. In some embodiments the statin is atorvastatin, rosuvastatin,simvastatin, pravastatin, lovastatin, fluvastatin, or pitavastatin. Inone aspect, the amount of atorvastatin administered per day is fromabout 10 mg to about 60 mg. In one aspect, the amount of rosuvastatinadministered per day is from about 5 mg to about 20 mg. In one aspect,the amount of simvastatin administered per day is from about 10 mg toabout 40 mg. In one aspect, the amount of pravastatin administered perday is from about 10 mg to about 80 mg. Combination of the otherpharmaceutical agents described herein with a statin and another agentinstead of the testosterone or testosterone ester are also contemplated.

In one aspect, the amount of lovastatin administered per day is fromabout 20 mg to about 40 mg. In one aspect, the amount of fluvastatinadministered per day is from about 20 mg to about 80 mg. In one aspect,the amount of pitavastatin administered per day is from about 1 mg toabout 4 mg. In one aspect, the amount of atorvastatin is from about 10mg to about 40 mg.

In one aspect, amount of rosuvastatin is from about 10 to about 20 mg.In one aspect, the amount of simvastatin is from about 10 mg to about 20mg. In one aspect, the amount of pravastatin is from about 10 mg toabout 20 mg. In one aspect, the amount of lovastatin is about 40 mg. Inone aspect, the amount of fluvastatin is from about 20 mg to about 40mg. In one aspect, the amount of pitavastatin is from about 1 mg toabout 3 mg.

Combination therapies (or monotherapies) can include administration ofmore or more of the following with an androgen receptor agonist ormodulator as described herein: a FXR agonist, a PPAR alpha or deltaagent, a lipid modulator, an anti-inflammatory (e.g., steroidal ornon-steroidal anti-inflammatory agents or other), an antioxidant, animmunomodulator, an insulin senitizer, an incretin mimetic, ahemorrheologic agent, an inhibitor of apoptosis, an agonist of theperoxisome proliferator, a thyroid hormone receptor modulator, an ASK1inhibitor, an Acetyl-CoA Carboxylase (ACC) inhibitor, afatty-acid/bile-acid Conjugate, galectin inhibitor, caspase proteaseinhibitor or a combination thereof in conjunction with the androgenreceptor agonist (e.g., testosterone ester like testosterone undecanoateor testosterone tridecanoate). Combination therapies also include e.g.,an androgen, testosterone, testosterone ester, testosterone undecanoate,testosterone tridecanoate with a glp-1 agonist or modulator (e.g.,liraglutide or semaglutide) or slgt-2 inhibitors (e.g., gliflozins,canagliflozin, ertugliflozin, dapagliflozin, empagliflozin, andsotagliflozin).

Subjects for Further Diagnostic/Prognostic Testing and Treatment

As described herein methods are provided for diagnosis/prognosis andtreatment of liver disease, particularly fatty liver disease, NAFLD,NASH, Cirrhosis, and symptoms thereof. The treatments anddiagnosis/prognosis can be performed for subject or samples obtainedfrom subjects as described in the below paragraph or as deemedappropriate by a medical professional. For example, the subject, asidentified below, is assessed for liver fat imaging (e.g., by MRI-PDFF)or liver stiffness (MRE) or a serum sample is assessed or for one ormore biomarkers described herein. This information is then used tofurther diagnose the subject and also can be used determine the mosteffective treatment.

In one aspect, the subject is a male hypogonadal subject. In one aspect,the subject is a male hypogonadal subject with class I, II, or IIIobesity. In one aspect, the subject is a male hypogonadal subject withclass I, II, or III obesity. In one aspect, the subject is a malehypogonadal subject having elevated or above-normal serum triglycerides.In one aspect, the subject is a male hypogonadal subject having elevatedor above normal serum AST or ALT levels. In one aspect, the subject is amale hypogonadal subject having class I, II, or III obesity and elevatedor above normal serum triglycerides. In one aspect, the subject is amale hypogonadal subject having class I, II, or III obesity and elevatedor above normal serum ALT or AST. In one aspect, the subject is a malehypogonadal subject having class I, II, or III obesity and elevated orabove normal serum triglycerides, and elevated or above normal serum ALTor AST.

Pharmaceutical Compositions

In certain embodiments, provided herein is a pharmaceutical compositioncomprising at least one steroidal compound (e.g., testosterone,dihydrotestosterone, estradiol, or analogs or prodrugs thereof) and atleast one pharmaceutically acceptable carrier. In specific embodiments,the steroidal compound is a steroidal androgen (e.g., testosterone,dihydrotestosterone, or prodrugs thereof). In some embodiments, thesteroidal compound is an alkylated, hydroxy-alkylated and/orhydroxy-alkoylated natural steroid (e.g., testosterone alkyl ester,dihydrotestosterone alkyl ester, estradiol alkyl ester, or the like). Incertain embodiments, analogs or prodrugs of testosterone include, e.g.,esters of testosterone. In specific embodiments, the esters oftestosterone include, e.g., alkyl (e.g., straight chain, branched,cyclic, unsaturated, partially saturated, fully saturated and the like)esters of testosterone. Specifically, alkyl esters of testosteroneinclude, by way of non-limiting example, lower alkyl esters (e.g.,testosterone C2-C13 alkyl esters such as testosterone propionate,testosterone enthanate, or testosterone undecanoate), or higher alkylesters (e.g., testosterone C14+ alkyl esters such as testosteronepalmitate). In further embodiments, the alkyl esters of testosteroneinclude, by way of non-limiting example, cycloalkylalkyl esters (e.g.,testosterone cypionate), cycloalkyl esters, and alkylcycloalkyl esters.In more specific embodiments, the testosterone alkyl ester istestosterone undecanoate. In some embodiments, the at least onesteroidal compound comprises (1) a testosterone lower alkyl ester (e.g.,testosterone propionate, testosterone enanthate, or testosteroneundecanoate); and (2) a testosterone higher alkyl ester (e.g.,testosterone palmitate). Generally, as used herein, a pharmaceuticalcomposition comprising a steroidal compound includes the disclosure of apharmaceutical composition comprising one or more steroidal compounds.

In some embodiments, dihydrotestosterone or a dihydrotestosterone estercan be used in place or in conjunction with a testosterone ester asdescribed herein. Exemplary dihydrotestosterone esters include, but arenot limited to, dihydrotestosterone propionate, dihydrotestosteroneenanthate, dihydrotestosterone cypionate, dihydrotestosteroneundecanoate, dihydrotestosterone decanoate, dihydrotestosteronedodecanoate, dihydrotestosterone tridecanoate, dihydrotestosteronetetradecanoate, and dihydrotestosterone palmitate.

In certain embodiments, any pharmaceutical composition described hereincomprises a therapeutically effective amount of at least one steroidalcompound (e.g., a testosterone alkyl ester, such as testosteroneundecanoate). In some embodiments, a therapeutically effective amount ofa steroidal compound (e.g., a testosterone alkyl ester, such astestosterone undecanoate) is divided into one or more oral dosage form.In some embodiments, the one or more of the oral dosage forms describedherein collectively comprise a therapeutically effective amount of atestosterone alkyl ester (e.g., testosterone undecanoate). Thus, in someembodiments, the therapeutically effective amount of a steroidalcompound (e.g., a testosterone alkyl ester, such as testosteroneundecanoate) within a pharmaceutical composition described herein mayvary when the pharmaceutical composition is administered in combinationwith another therapy. Furthermore, therapeutically effective amounts ofa formulation may depend on the specific formulation within which the atleast one steroidal compound is found. For example, in some embodiments,more than one steroidal compound is present in a pharmaceuticalcomposition described herein. Thus, when there is a combination ofsteroidal compounds, in certain instances one or both of the steroidalcompounds present has a therapeutically effective amount that is lowerthan is required when the steroidal compounds are administeredseparately or alone. In some embodiments, a pharmaceutical compositiondescribed herein further comprises an adjuvant, which, in certaininstances, allows for a lower amount of a steroidal compound to beutilized as a therapeutically effective amount.

As described in typical total daily dose ranges for adult male andfemale subjects are given for testosterone undecanoate and testosteronetridecanoate. Based on the doses, doses for other testosterone esterscan be estimated on the T-equivalent dose which is determined e.g., bythe amount of testosterone per testosterone undecanoate molecule. Forexample, for calculation purposes, 1 mg of T is equivalent to: 1.39 mgT-enanthate; 1.58 mg T-undecanoate; 1.43 mg T-cypionate ab so on.Although the conversion is not exact due to various properties, askilled artisan understand how to estimate a dose of one testosteroneester for another testosterone ester based on this calculation.

In certain embodiments, a pharmaceutical composition described hereincomprises about 1 mg to about 1.5 g, about 10 mg to about 1000 mg, orabout 10 mg to about 200 mg of a steroidal compound (e.g., atestosterone alkyl ester, such as testosterone undecanoate). In specificembodiments, a pharmaceutical composition described herein comprisesabout 10 mg to about 50 mg, about 15 mg to about 40 mg, about 20 mg, toabout 30 mg, or about 25 mg of steroidal compound (e.g., a testosteronealkyl ester, such as testosterone undecanoate). In other embodiments, apharmaceutical composition described herein comprises about 70 mg toabout 150 mg, about 80 mg to about 140 mg, about 90 mg to about 140 mg,about 100 mg to about 130 mg, about 110 mg to about 130 mg, about 110 mgto about 120 mg, about 130 mg to about 180 mg, about 180 mg to about 230mg, about 230 mg to about 280 mg, about 280 mg to about 330 mg, about330 mg to about 380 mg, about 380 mg to about 430 mg, about 430 mg toabout 480 mg, about 480 mg to about 530 mg, or about 530 mg to about 580mg of a steroidal compound (e.g., a testosterone alkyl ester, such astestosterone undecanoate). In some embodiments, a pharmaceuticalcomposition described herein comprises about 0.1 mg to about 10 mg of asteroidal compound (e.g., a testosterone alkyl ester such astestosterone undecanoate) per kg of an individual to whom the oraldosage form is to be administered. In certain embodiments, apharmaceutical composition described herein comprises an amount of asteroidal compound (e.g., a testosterone alkyl ester, such astestosterone undecanoate) sufficient to provide about 1 mg to about 1 g,about 5 mg to about 500 mg, about 10 mg to about 300 mg, or about 20 toabout 250 mg of a steroidal compound (e.g., a testosterone alkyl ester,such as testosterone undecanoate) to an individual upon once a day,twice a day, three times a day, or four times a day oral administration.

In some embodiments, the at least one pharmaceutically acceptablecarrier is any carrier suitable for delivering an efficacious amount ofa steroidal compound, e.g., a testosterone alkyl ester, to anindividual. In some embodiments, the at least one pharmaceuticallyacceptable carrier is or comprises a hydrophilic carrier (e.g., ahydrophilic surfactant or hydrophilic additive). In certain embodiments,the at least one pharmaceutically acceptable carrier is a lipophiliccarrier (e.g., a lipophilic surfactant or lipophilic additive). In someembodiments, the at least one pharmaceutically acceptable carrier is ahydrophilic carrier (e.g., a hydrophilic surfactant or hydrophilicadditive) and a lipophilic carrier (e.g., a lipophilic surfactant orlipophilic additive). In certain embodiments, the hydrophilic carrier isa hydrophilic triglyceride. In specific embodiments, the hydrophilictriglyceride is a polyoxylated castor oil, or a polyoxylatedhydrogenated castor oil. In some embodiments, any pharmaceuticalcomposition provided herein consists essentially of a lipophilic carrieror combination of lipophilic carriers. In certain embodiments, anypharmaceutical composition provided herein comprises a lipophiliccarrier and less than 10% w/w, less than 5% w/w or is substantially freeof a hydrophilic carrier. In certain embodiments, any pharmaceuticalcomposition provided herein comprises a lipophilic carrier and less than10% w/w, less than 5% w/w or is substantially free of a hydrophiliccarrier. In some embodiments, the pharmaceutical composition comprisinga carrier (e.g., a hydrophilic carrier and/or a lipophilic carrier), thepharmaceutical composition is a solid, a semi-solid, a gel, a jelly, apaste, or the like. In certain embodiments, e.g., wherein apharmaceutical composition comprising a hydrophilic carrier and/or alipophilic carrier, a viscosity enhancing agent or a solidifying agentis utilized to afford a pharmaceutical composition that is a solid, asemi-solid, a gel, a jelly, a paste, or the like. Thus, in certainembodiments, the at least one pharmaceutically acceptable carrier is ahydrophilic carrier (e.g., a hydrophilic surfactant or hydrophilicadditive) and a viscosity enhancing or solidifying agent. In certainembodiments, the at least one pharmaceutically acceptable carrier is alipophilic carrier (e.g., a lipophilic surfactant or lipophilicadditive) and a viscosity enhancing or solidifying agent. In someembodiments, the at least one pharmaceutically acceptable carrier is orcomprises a hydrophilic carrier (e.g., a hydrophilic surfactant orhydrophilic additive), a lipophilic carrier (e.g., a lipophilicsurfactant or lipophilic additive), and a viscosity enhancing orsolidifying agent. In some embodiments, the at least onepharmaceutically acceptable carrier is or comprises an amphiphilic orzwitterionic carrier (e.g., a ampiphilic surfactant or ampiphilicadditive). In certain embodiments, the pharmaceutically acceptablecarrier is any carrier suitable for achieving one or more of thepharmacokinetic and/or pharmacodynamic profiles set forth herein.

Additives useful herein include chemical substances that are generallypharmacologically inactive. Further, the additive may be solid, liquidor semi-solid in nature at about ambient room temperature. Furthermore,the additive may be hydrophilic or lipophilic. In certain instances, a“hydrophilic additive” is a substance that has at least one polar sidegroup in its chemical structure which will attract water; whereas a“lipophilic additive” exhibits a tendency to repel water.

In some embodiments, the hydrophilic or lipophilic additive is containedwithin the components forming a composition and/or pharmaceutical dosageform thereof. In certain embodiments, the hydrophilic or lipophilicadditive is in an encapsulation coat in compositions. Alternatively, theadditives can be comprised in the pharmaceutical composition but not aspart of the composition itself. Specific, non-limiting examples ofadditives are described below.

Suitable additives include any additive that can facilitate theprocesses involving the preparation of a pharmaceutical compositionand/or dosage form described herein. In some instances, such additivesinclude those commonly utilized to facilitate the processes involvingthe preparation of a composition and/or a pharmaceutical dosage formdescribed herein. These processes include agglomeration, air suspensionchilling, air suspension drying, balling, coacervation, comminution,compression, pelletization, cryopelletization, encapsulation, extrusion,granulation, homogenization, inclusion complexation, lyophilization,nanoencapsulation, melting, mixing, molding, pan coating, solventdehydration, sonication, spheronization, spray chilling, spraycongealing, spray drying, or other processes known in the art. Incertain instances, the additive is optionally pre-coated orencapsulated. Suitable additives are optionally utilized to influencethe drug release from the composition and/or pharmaceutical dosage form.

Suitable additives utilized in various embodiments described hereininclude, by way of non-limiting example, adsorbing agents,anti-adherents, anticoagulants, antifoaming agents, antioxidants,anti-caking agents, anti-static agents, binders, bile acids, bufferants,bulking agents, chelating agents, coagulants, colorants, co-solvent,opaquants, congealing agents, coolants, cryoprotectants, diluents,dehumidifying agents, desiccants, desensitizers, disintegrants,dispersing agents, enzyme inhibitors, glidants, fillers, hydratingagent, super disintegrants, gums, mucilages, hydrogen bonding agents,enzymes, flavorants, humectants, humidifying agents, lubricant oils,ion-exchange resins, lubricants, plasticizers, pH modifying agents,preservatives, solidifying agent, solvents, solubilizers, spreadingagent sweeteners, stabilizers, surface area enhancing agents, suspendingagent, thickeners, viscosity increasing agents, waxes and mixturesthereof.

Some non-limiting examples of the hydrophilic or lipophilic additivessuitable for the current invention are as follows:

Alcohols and/or Polyols (e.g. ethanol, isopropanol, butanol, benzylalcohol, ethylene glycol, propylene glycol, glycerol, sorbitol,mannitol, dimethyl isosorbide, polyethylene glycol, fatty acid alcohol,vinyl alcohol polypropylene glycol, polyvinylalcohol, tocopherols,cellulose cyclodextrins, other derivatives, forms, mixtures thereof, orthe like); ethers of polyethylene glycols having an average molecularweight of about 200 to about 20,000 (e.g. tetrahydrofurfuryl alcohol PEGether, methoxy PEG, or the like); Amides (e.g. 2-pyrrolidone,2-piperidone, 8-caprolactam, N-alkylpyrrolidone,N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam,dimethylacetamide, polyvinylpyrrolidone and the like.); Esters (e.g.ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyltributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethylbutyrate, triacetin, propylene glycol monoacetate, propylene glycoldiacetate, 8-caprolactone and isomers thereof, 6-valerolactone andisomers thereof, β-butyrolactone and isomers thereof, and otheradditives known in the art, such as dimethyl acetamide, dimethylisosorbide, N-methylpyrrolidones, monooctanoin, diethylene glycolmonoethyl ether, or the like); Amino acids (e.g. P-aminobenzamidine,sodium glycocholate) mesylate; Amino acids and modified amino acids(e.g. aminoboronic acid derivatives and n-acetylcysteine; Peptides andmodified peptides (e.g. bacitracin, phosphinic acid dipeptidederivatives, pepstatin, antipain, leupeptin, chymostatin, elastin,bestatin, phoshporamindon, puromycin, cytochalasin potatocarboxypeptidase inhibitor, amastatin, or the like); Polypeptide proteaseinhibitors; Mucoadhesive polymers (e.g. polyacrylate derivatives,chitosan, cellulosics, chitosan-EDTA, chitosan-EDTA-antipain,polyacrylic acid, carboxymethyl cellulose etc.); or the like; orcombinations thereof.

Some more examples of suitable additives for compositions and/or dosageforms described herein include, by way of non-limiting example, talc,magnesium stearate, silica (e.g. fumed silica, micronized silica,magnesium aluminum silicate etc.) and/or derivatives, polyethyleneglycols, surfactants, waxes, oils, cetyl alcohol, polyvinyl alcohol,stearic acid, stearic acid salts, stearic acid derivatives, starch,hydrogenated vegetable oils, hydrogenatied castor oils, sodium benzoate,sodium acetate, leucine, PEG, alkyl sulfate salts; acetylatedmonoglycerides; long-chain alcohols; silicone derivatives; butylatedhydroxy toluene (BHT), butylated hydroxyl anisole (BHA), gallic acid,propyl gallate, ascorbic acid, ascorbyl palmitate,4-hydroxymethyl-2,6-di-tert-butyl phenol, dry starch, dry sugars,polyvinyl pyrrolidones, starch paste, methacrylic copolymers, bentonite,sucrose, polymericcellulose derivatives, shellac, sugar syrup; cornsyrup; polysaccharides, acacia, tragacanth, guar gum, xanthan gums;alginates; gelatin; gelatin hydrolysate; agar; sucrose; dextrose; PEG,vinyl pyrrolidone copolymers, poloxamers; pregelatinized starch,sorbitol, glucose); acetic acid, hydrochloric acid, hydrobromic acid,hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid,acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonicacid, amino acids, ascorbic acid, benzoic acid, boric acid, butyricacid, carbonic acid, citric acid, fatty acids, formic acid, fumaricacid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lacticacid, maleic acid, methanesulfonic acid, oxalic acid,para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid,salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid,thioglycolic acid, toluenesulfonic acid and uric acid, vinegar,pharmaceutically acceptable bases, such as an amino acid, an amino acidester, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodiumhydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesiumhydroxide, magnesium aluminum silicate, synthetic aluminum silicate,synthetic hydrotalcite, magnesium aluminum hydroxide,diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine,triethylamine, triisopropanolamin; salt of a pharmaceutically acceptablecation and an anion; EDTA and EDTA salts; titanium dioxide, food dyes,lakes, natural vegetable colorants, iron oxides, silicates, sulfates,magnesium hydroxide and aluminum hydroxide; halogenated hydrocarbons,trichloroethane, trichloroethylene, dichloromethane,fluorotrichloromethane, diethylether, trehelose, phosphates, citricacid, tartaric acid, gelatin, dextran and mannitol, lactose, mannitol,sodium chloride, potassium chloride, spray-dried lactose, hydrolyzedstarches, directly compressible starch, microcrystalline cellulose,cellulosic derivatives, sorbitol, sucrose, sucrose-based materials,calcium sulfate, dibasic calcium phosphate, dextrose, croscarmellosesodium, starch, starch derivatives, clays, gums, cellulose, cellulosederivates, alginates, crosslinked polyvinylpyrrolidone, sodium starchglycolate and microcrystalline cellulose, magnesium oxide, magnesiumcarbonates; desensitizers, spray-dried flavors, essential oils, ethylvanillin, styrene/divinyl benzene copolymers, quaternary ammoniumcompounds, polyethylene glycol, citrate esters (such as triethylcitrate, acetyl triethyl citrate, acetyltributyl citrate), acetylatedmonoglycerides, glycerin, triacetin, propylene glycol, phthalate esters(e.g., diethyl phthalate, dibutyl phthalate), castor oil, sorbitol anddibutyl sebacate, ascorbic acid, boric acid, sorbic acid, benzoic acid,and salts thereof, parabens, phenols, benzyl alcohol, and quaternaryammonium compounds; alcohols, ketones, esters, chlorinated hydrocarbonswater; sweeteners, (e.g. maltose, sucrose, glucose, sorbitol, glycerinand dextrins, aspartame, saccharine, saccharine salts, glycyrrhizin),viscosity modifiers, sugars, polyvinylpyrrolidone, cellulosics,polymers, gums and/or alginates.

Additives can also be materials such as proteins (e.g., collagen,gelatin, Zein, gluten, mussel protein, lipoprotein); carbohydrates(e.g., alginates, carrageenan, cellulose derivatives, pectin, starch,chitosan); gums (e.g., xanthan gum, gum arabic); spermaceti; natural orsynthetic waxes; carnuaba wax; fatty acids (e.g., stearic acid,hydroxystearic acid); fatty alcohols; sugars; shellacs, such as thosebased on sugars (e.g., lactose, sucrose, dextrose) or starches;polysaccharide-based shellacs (e.g., maltodextrin and maltodextrinderivatives, dextrates, cyclodextrin and cyclodextrin derivatives);cellulosic-based polymers (e.g., ethyl cellulose, methyl cellulose,microcrystalline cellulose, sodium carboxymethyl cellulose,hydroxypropylmethyl cellulose, ethyl cellulose, hydroxypropyl cellulose,HPMC acid succinates, cellulose acetate, cellulose nitrate, celluloseacetate butyrate, cellulose acetate trimellitate, carboxymethylethylcellulose, hydroxypropylmethyl cellulose phthalate), shellacs;inorganics, such as dicalcium phosphate, hydroxyapitite, tricalciumphosphate, talc and titania; polyols, such as mannitol, xylitol andsorbitol; polyethylene glycol esters; and polymers, such as alginates,poly(lactide coglycolide), gelalin, crosslinked gelatin, and agar-agar.

It should be appreciated that there is considerable overlap between theabove-listed additives in common usage, since a given hydrophilic orlipophilic additive is often classified differently by differentpractitioners in the field, or is commonly used for any of severaldifferent or overlapping functions. Thus, the above-listed hydrophilicor lipophilic additives should be taken as merely exemplary, and notlimiting, of the types of additives that can be included in compositionsof the present invention. In certain embodiments, the amounts of suchadditives are optionally adjusted and/or determined by one skilled inthe art, according to the particular properties desired.

In certain embodiments, the at least one pharmaceutically acceptablecarrier comprises at least one hydrophilic carrier (e.g., hydrophilicsurfactant). In some embodiments, the hydrophilic carrier is apolyoxylated glyceride (e.g., mono-, di-, or tri-glyceride), apolyoxylated vegetable oil, a polyoxylated hydrogenated vegetable oil, apolyoxylated fatty acid (mono-, or di-substituted), combinationsthereof, or the like. In certain embodiments, the at least onepharmaceutically acceptable carrier comprises or further comprises alipophilic carrier. Lipophilic carriers are selected from, by way ofnon-limiting example, a lipophilic surfactant, a vegetable oil (e.g.,castor oil), a fatty acid, a fatty alcohol, a glyceride (e.g., mono-,di-, or tri-glyceride), a hydrogenated vegetable oil, a Vitamin Ecompound (e.g., d,l-α-tocopherol), a trigliceride, a fatty acid,polyoxylated fatty acid, polyoxylated triglyceride, polyoxylatedvegetable oil, or combinations thereof. In some embodiments,polyoxylated compounds include polyethoxylated compounds.

In certain embodiments, the at least one hydrophilic carriers make upabout 1% to about 99% w/w, about 2% to about 80% w/w, about 2% to about50% w/w, or about 10% to about 40% w/w of any pharmaceutical compositiondescribed herein. In some embodiments, lipophilic carriers make up about1% w/w to about 99% w/w, about 2% to about 80% w/w, about 10% w/w toabout 80% w/w, about 30% w/w, to about 80% w/w, or about 40% to about80% w/w of any pharmaceutical composition described herein.

In specific embodiments, provided herein is a pharmaceutical composition(e.g., a delayed release dosage form) comprising a hydrophilic carrier.In more specific embodiments, the hydrophilic carrier is or comprises apolyoxylated vegetable oil (e.g., a polyoxylated, hydrogenated vegetableoil). In still more specific embodiments, a polyoxylated vegetable oilis a polyoxylated castor oil (e.g., a polyoxylated, hydrogenated castoroil). In certain embodiments, the lipidic and/or lipophilic carrier isnot a C6-C18 fatty acid. In some embodiments, the lipophilic carrier isa C20+ fatty acid. In some embodiments, the lipidic and/or lipophiliccarrier is not a fatty acid or an un-modified (e.g., non-polyoxylated)vegetable oil. In more specific embodiments, the lipidic and/orlipophilic carrier is not oleic acid or castor oil. In certain specificembodiments provided herein is a pharmaceutical composition (e.g., adelayed release dosage form) comprising an amphiphilic carrier. In morespecific embodiments, the amphiphilic carrier is or comprises azwitterionic choline (e.g., phosphatidylcholine). In some specificembodiments, provided herein is a pharmaceutical composition (e.g., adelayed release dosage form) comprising a lipophilic carrier. In morespecific embodiments, the lipophilic carrier is or comprises, by way ofnon-limiting example, a mono-, di- or triglyceride (e.g., glycerolmonolinoleate).

In some embodiments, the at least one pharmaceutically acceptablecarrier comprises at least one hydrophilic carrier, and at least onelipidic and/or lipophilic carrier. In further embodiments, the at leastone pharmaceutically acceptable carrier comprises at least onehydrophilic carrier, at least one lipidic and/or lipophilic carrier, andat least one viscosity enhancer or solidifying agent. In someembodiments, the solidifying agent is a polyethylene glycol (e.g., ahigh molecular weight polyethylene glycol, such as PEG 8000). Inspecific embodiments, a pharmaceutical composition described hereincomprises, along with a steroidal agent (e.g., a testosterone alkylester), a hydrogenated and polyoxylated castor oil and a polyethyleneglycol. In more specific embodiments, the pharmaceutical compositioncomprising a hydrogenated and polyoxylated castor oil and a polyethyleneglycol further comprises an additional lipidic and/or lipophiliccarrier. In some embodiments, the additional lipidic and/or lipophiliccarrier is a monoglyceride, a diglyceride, a Vitamin E compound, or acombination thereof.

In certain embodiments, pharmaceutical compositions described hereininclude oral dosage forms or delayed release oral dosage forms of any ofTables A to Q. In Tables A to Q, approximate weight percentages of thecompositions formulated into the capsules are provided. In specificembodiments, the steroidal compound of any of Capsules A1 to Q2comprises an alkyl ester testosterone (e.g., testosterone undecanoate).In certain instances, provided in the tables are non-limiting gradesand/or sources of components utilized. Disclosure provided in Tables Ato Q is not limited to the grades and/or sources described. It is notedthat any testosterone ester can be used in place of any specifictestosterone ester disclosed in these tables (e.g., testosteronetridecanoate can be used in place of testosterone undecanoate or twotestosterone esters can be used e.g., testosterone undecanoate andtestosterone tridecanoate).

TABLE A Capsule Capsule A1 A2 Component % w/w % w/w Steroidal Compound(~10-1000 mg) 1-50 10-30 Hydrophilic Carrier 1-90 10-30 LipophilicCarrier 1-90 40-70 Solidifying Agent (additive) 1-20  5-10

TABLE B Capsule Capsule B1 B2 Component % w/w % w/w Testosteroneundecanoate (~10-1000 mg)  1-50 15 Polyoxyl 40 Hydrogenated Castor Oil,NF  1-50 16 Glycerol Monolinoleate, NF (Maisine 35-1) 30-90 63Polyethylene Glycol 8000, USP  1-20 6

TABLE C Capsule Capsule C1 C2 Component % w/w % w/w Testosteroneundecanoate (~10-1000 mg)  1-50 25 Polyoxyl 35 Castor Oil, NF  1-50 21Vitamin E, USP (d, l-α-tocopherol) 30-90 48 Polyethylene Glycol 8000,USP  1-20 6

TABLE D Capsule Capsule D1 D2 Component % w/w % w/w Steroidal Compound(~10-1000 mg) 15 10-30 Lauryl macrogol glyceride 51 20-90 (Gelucire44/14) Stearoyl macrogol glyceride 34 10-90 (Gelucire 50/13)

TABLE E Capsule Capsule E1 E2 Component % w/w % w/w Steroidal Compound(~10-1000 mg) 20 10-30 C8-C18 macrogol glyceride 35 10-70 (Gelucire43/01) Polyglyceryl-3-oleate (CAPROL 3GO) 45  5-60

TABLE F Capsule Capsule F1 F2 Component % w/w % w/w Steroidal Compound(~10-1000 mg) 15 10-25 Lauryl macrogol glyceride 40  5-80 (Gelucire44/14) Vitamin E 30  2-60 Hypromellose 15  5-25 (Methocel K100 M LV, CR)

TABLE G Capsule Capsule G1 G2 Component % w/w % w/w Steroidal Compound(~10-1000 mg) 15 10-30 PEG-40 hydrogenated Castor Oil 60  5-80(Cremophor ® RH40) Polyethylene glycol 8000 15  5-40 Hypromellose 10 5-25 (Methocel K100 M LV, CR)

TABLE H Capsule Capsule H1 H2 Component % w/w % w/w Steroidal Compound(~10-1000 mg) 15 10-30 Corn Glycerides (Maisine 35-1) 60  5-90Polyethylene glycol 8000 20  5-70

TABLE I Capsule Capsule I1 I2 Component % w/w % w/w Steroidal Compound(~10-1000 mg) 25 10-30 PEG-40 hydrogenated Castor Oil 15 5-80(Cremophor ® RH40) Vitamin E 20 2-60 Corn Glycerides (Maisine 35-1) 305-50 Polyethylene Glycol 8000 10 5-20

TABLE J Capsule J1 Capsule J2 Component % w/w % w/w Steroidal Compound(~10-1000 mg) 15 10-30 Hydrogenated vegetable oil 50  2-80 Polyethyleneglycol 8000 35  2-80

TABLE K Capsule K1 Capsule K2 Component % w/w % w/w Steroidal Compound(~10-1000 mg) 50 30-60 Corn Glycerides (Maisine 35-1) 50 30-60

TABLE L Capsule L1 Capsule L2 Component % w/w % w/w Steroidal Compound(~10-1000 mg) 40 30-60 Fish Oil 50 30-60 Vitamin E 10  3-15

TABLE M Capsule M1 Capsule M2 Component % w/w % w/w Steroidal Compound(~10-1000 mg) 40 30-60 Omega-3-acid esters 50 30-60 Polyethylene glycol8000  5  3-15

TABLE N Capsule N1 Capsule N2 Component % w/w % w/w Testosteroneundecanoate  5-30 10-20 Polyoxyl 40 Hydrogenated Castor Oil,  5-30 10-20NF Glyceryl Monolinoleate, NF (Maisine 50-90 55-70 35-1) PolyethyleneGlycol 8000, USP  1-15 3-8

TABLE O Capsule O1 Capsule O2 Component % w/w % w/w Testosteroneundecanoate 10-40 20-30 Polyoxyl 35 Castor Oil, NF 10-30 15-25 VitaminE, USP (d,l-α-tocopherol) 30-70 40-55 Polyethylene Glycol 8000, USP 1-15 3-8

TABLE P Capsule P1 Capsule P2 Component % w/w % w/w Testosteroneundecanoate 10-40 20-25 Vitamin E Polyethylene Glycol 10-40 20-25Succinate, NF Vitamin E, USP (d,l-tocopherol) 15-60 30-40 PolyethyleneGlycol 8000, USP  1-10 2-6 Hypromellose (100 cP, K100  5-40 15-25Premium LV)

TABLE Q Capsule Q1 Capsule Q2 Component % w/w % w/w Testosteroneundecanoate 10-40 20-25 Vitamin E Polyethylene Glycol 10-40 20-25Succinate, NF Vitamin E, USP (d,l-tocopherol) 15-60 30-40 PolyethyleneGlycol 8000, USP  1-10 2-6 Hypromellose (4,000 cP, K4M)  5-40 15-25

It is noted that the above compositions (or elsewhere) can also beprepared without any of the specific solidifying agents and used in themethods described herein.

In certain embodiments, any pharmaceutical composition described herein,e.g., a pharmaceutical composition of any of Tables A to Q can beprepared by (i) combining and heating all ingredients until a moltenmixture is obtained (e.g., 50-70° C.); and (ii) encapsulating an amountof molten mixture comprising a select dose (e.g., a therapeuticallyeffective amount or a partial dose of a therapeutically effectiveamount) of steroidal compound to obtain an oral dosage form. In certaininstances, the molten mixture is spray-congealed to obtain beads. Insome instances, the molten mixture is sprayed onto inert cores (e.g.,sugar spheres) to obtain coated cores. In certain embodiments, suchbeads, cores, or similar forms are encapsulated or otherwise formulatedto provide an oral dosage form. In some instances, the molten mixture isadmixed, uniformly dispersed, or granulated over a carrier andcompressed into a tablet dosage form. In certain embodiments, prior tocompression, the molten mixture/carrier composition is further mixedwith one or more pharmaceutical aid including, by way of non-limitingexample, glidants, lubricants, binders, or the like. In someembodiments, the carrier is a therapeutically inert carrier such as, byway of non-limiting example, microcrystalline cellulose, starch,lactose, or the like.

In some embodiments, compositions described herein (e.g., compositionsset forth in Tables K to M), are optionally filled into a delayedrelease capsule or shell, or are otherwise coated or encapsulated with adelayed release coat.

Carriers

Provided herein are pharmaceutical compositions comprising a steroidalcompound (e.g., one or more testosterone alkyl ester (e.g., testosteroneester), such as testosterone undecanoate) and at least onepharmaceutically acceptable carrier. In certain embodiments, the atleast one pharmaceutically acceptable carrier comprises at least onehydrophilic carrier (e.g., hydrophilic surfactant or additive), at leastone lipophilic carrier (e.g., lipophilic surfactant or additive), and/orat least one viscosity enhancer or solidifying agent. In specificembodiments, the at least one pharmaceutically acceptable carrier is ahydrophilic carrier. In more specific embodiments, the at least onepharmaceutically acceptable carrier comprises or further comprises alipophilic carrier. In further embodiments, the at least onepharmaceutically acceptable carrier comprises at least one hydrophiliccarrier, at least one lipidic and/or lipophilic carrier, and at leastone viscosity enhancer or solidifying agent.

In certain embodiments, hydrophilic carriers include, by way ofnon-limiting example, a hydrophilic surfactant. In various instances,hydrophilic surfactants are used to provide any one or more of severaladvantageous characteristics to the compositions, including, by way ofnon-limiting example: increased solubility of the active ingredient inat least one of the fractions of the carrier that is a solid carrier:improved dissolution of the active ingredient; improved dispersionand/or dissolution of the lipidic carrier; improved solubilization ofthe active ingredient upon dissolution; enhanced absorption and/orbioavailability of the active ingredient, particularly a hydrophilic,hydrophobic, or lipophilic active ingredient; and improved stability,both physical and chemical, of the active ingredient. In variousembodiments, the hydrophilic surfactant includes either a singlehydrophilic surfactant or a mixture of hydrophilic surfactants.Hydrophilic surfactants also include both ionic or non-ionicsurfactants.

In some embodiments, lipophilic carriers include or further include, byway of non-limiting example, one or more lipophilic surfactant,including one or more lipophilic surfactant, one or more mono-, di-, ortriglyceride, or mixtures thereof. In various instances, lipophilicsurfactants provide any one or more of the advantageous characteristicslisted above for hydrophilic surfactants, and/or enhance the function ofother (e.g., hydrophilic) surfactants present in the pharmaceuticalcomposition.

The terms “hydrophilic” and “lipophilic” are relative terms.Hydrophilicity and/or lipophilicity are determined in any mannersuitable. In one instances, an empirical parameter is used tocharacterize the relative hydrophilicity and lipophilicity of thecarriers described herein. For example, in one manner, thehydrophilicity and/or lipophilicity non-ionic amphiphilic compounds isthe hydrophilic-lipophilic balance (the “HLB” value). Carriers orsurfactants with lower HLB values are more lipophilic, and have greatersolubility in oils, whereas surfactants with higher HLB values are morehydrophilic, and have greater solubility in aqueous mediums. Thismeasure is suitable for the surfactants described herein because,generally, surfactants are amphiphilic as they comprise both a polarmoiety (e.g., a polar non-charged or charged moiety) and a lipophilicmoiety (e.g., an aliphatic group).

Using HLB values as a rough guide, hydrophilic surfactants are generallyconsidered to be those compounds having an HLB value greater than about10, as well as non-ionic, anionic, cationic, or zwitterionic compoundsfor which the HLB scale is not generally applicable. Similarly,lipophilic surfactants are compounds having an HLB value less than about10.

It should be appreciated that the HLB value of a surfactant is merely arough guide generally used to enable formulation of industrial,pharmaceutical and cosmetic emulsions. For many important surfactants,including several polyethoxylated surfactants, it has been reported thatHLB values can differ by as much as about 8 HLB units, depending uponthe empirical method chosen to determine the HLB value (Schott, J.Pharm. Sciences. 79(1), 87-88 (1990)). Likewise, for certainpolypropylene oxide containing block copolymers (poloxamers, availablecommercially as PLURONIC® surfactants, BASF Corp.), the HLB values arenot always authoritative indicators of the true physical chemical natureof the compounds. Finally, commercial surfactant products are generallynot pure compounds, but are often complex mixtures of compounds, and theHLB value reported for a particular compound may more accurately becharacteristic of the commercial product of which the compound is amajor component. Different commercial products having the same primarysurfactant component can, and typically do, have different 1LB values.In addition, a certain amount of lot-to-lot variability is expected evenfor a single commercial surfactant product. Thus, keeping theseconsiderations involved, a person of ordinary skill in the art is ableto utilize HLB values and the identity of a given product to determinesurfactants for suitable lipophilicity and/or hydrophilicity for use inthe pharmaceutical compositions described herein.

As used herein, useful surfactants include any surfactant that ispharmaceutically acceptable and is suitable for use in a pharmaceuticalcomposition. Suitable surfactants include anionic, cationic,zwitterionic and non-ionic surfactants. Provided herein (e.g., in theTables) are several general classes of surfactants. The HLB values givenin the Tables below generally represent the HLB value as reported by themanufacturer of the corresponding commercial product. In cases wheremore than one commercial product is listed, the HLB value in the Tablesis the value as reported for one of the commercial products, a roughaverage of the reported values, or a value that, in the judgment of thepresent inventors, is more reliable.

Surfactants described in the Tables are illustrative and are provided asnon-limiting examples. For example, refined, distilled or fractionatedsurfactants, purified fractions thereof, or re-esterified fractions, arealso within the scope of surfactants described herein, although they arenot specifically listed in the Tables.

In some embodiments, surfactants described herein include polyoxylatedfatty acids, such as polyethoxylated fatty acids (i.e., PEG-fatty acidesters). Provided in Table 1 is a list of illustrative and non-limitingexamples of polyethoxylated fatty acid monoester surfactants.

TABLE 1 PEG-Fatty Acid Monoester Surfactants COMMERCIAL PRODUCT COMPOUND(Supplier) HLB PEG 4-100 monolaurate Crodet L series (Croda) >9 PEG4-100 monooleate Crodet O series (Croda) >8 PEG 4-100 monostearateCrodet S series (Croda), >6 Myrj Series (Atlas/ICI) PEG 400 distearateCithrol 4DS series (Croda) >10 PEG 100, 200, 300 Cithrol ML series(Croda) >10 monolaurate PEG 100, 200, 300 Cithrol MO series (Croda) >10monooleate PEG 400 dioleate Cithrol 4DO series (Croda) >10 PEG 400-1000Cithrol MS series (Croda) >10 monostearate PEG-1 stearate Nikkol MYS-IEX(Nikko), 2 Coster KI (Condea) PEG-2 stearate Nikkol MYS-2 (Nikko) 4PEG-2 oleate Nikkol MYO-2 (Nikko) 4.5 PEG-4 laurate MAPEG ® 200 ML(PPG), 9.3 KESSCO ® PEG 200ML (Stepan), LIPOPEG 2L (LIPO Chem.) PEG-4oleate MAPEG ® 200 MO (PPG), 8.3 KESSCO ® PEG200 MO (Stepan) PEG-4stearate KESSCO ® PEG 200 MS (Stepan), 6.5 Hodag 20 S (Calgene), NikkolMYS-4 (Nikko) PEG-5 stearate Nikkol TMGS-5 (Nikko) 9.5 PEG-5 oleateNikkol TMGO-5 (Nikko) 9.5 PEG-6 oleate Algon OL 60 (Auschem SpA), 8.5KESSCO ® PEG 300 MO (Stepan), Nikkol MYO-6 (Nikko), Emulgante A6(Condea) PEG-7 oleate Algon OL 70 (Auschem SpA) 10.4 PEG-6 laurateKESSCO ® PEG300 ML (Stepan) 11.4 PEG-7 laurate Lauridac 7 (Condea) 13PEG-6 stearate KESSCO ® PEG300 MS (Stepan) 9.7 PEG-8 laurate MAPEG ® 400ML (PPG), 13 LIPOPEG 4DL(Lipo Chem.) PEG-8 oleate MAPEG ® 400 MO (PPG),12 Emulgante A8 (Condea); KESSCO PEG 400 MO (Stepan) PEG-8 stearateMAPEG ® 400 MS (PPG), Myrj 45 12 PEG-9 oleate Emulgante A9 (Condea) >10PEG-9 stearate Cremophor 59 (BASF) >10 PEG-10 laurate Nikkol MYL-10(Nikko), 13 Lauridac 10 (Croda) PEG-10 oleate Nikkol MYO-10 (Nikko) 11PEG-10 stearate Nikkol MYS-10 (Nikko), 11 Coster K100 (Condea) PEG-12laurate KESSCO ® PEG 600ML (Stepan) 15 PEG-12 oleate KESSCO ® PEG 600MO(Stepan) 14 PEG-12 ricinoleate (CAS #9004-97-1) >10 PEG-12 stearateMAPEG ® 600 MS (PPG), 14 KESSCO ® PEG 600MS (Stepan) PEG-15 stearateNikkol TMGS-15 (Nikko), 14 Koster K15 (Condea) PEG-15 oleate NikkolTMGO-15 (Nikko) 15 PEG-20 laurate KESSCO ® PEG 1000 ML (Stepan) 17PEG-20 oleate KESSCO ® PEG 1000 MO 15 (Stepan) PEG-20 stearate MAPEG ®1000 MS (PPG), 16 KESSCO ® PEG 1000 MS (Stepan), Myrj 49 PEG-25 stearateNikkol MYS-25 (Nikko) 15 PEG-32 laurate KESSCO ® PEG 1540 ML (Stepan) 16PEG-32 oleate KESSCO ® PEG 1540 MO 17 (Stepan) PEG-32 stearate KESSCO ®PEG 1540 MS (Stepan) 17 PEG-30 stearate Myrj 51 >10 PEG-40 laurateCrodet L40 (Croda) 17.9 PEG-40 oleate Crodet O40 (Croda) 17.4 PEG-40stearate Myrj 52, Emerest ® 2715 (Henkel), >10 Nikkol MYS-40 (Nikko)PEG-45 stearate Nikkol MYS-45 (Nikko) 18 PEG-50 stearate Myrj 53 >10PEG-55 stearate Nikkol MYS-55 (Nikko) 18 PEG-100 oleate Crodet 0-100(Croda) 18.8 PEG-100 stearate Myrj 59, Arlacel 165 (ICI) 19 PEG-200oleate Albunol 200 MO (Taiwan Surf.) >10 PEG-400 oleate LACTOMUL(Henkel), >10 Albunol 400 MO (Taiwan Surf.) PEG-600 oleate Albunol 600MO (Taiwan Surf) >10

Furthermore, in some embodiments, surfactants described herein include,by way of non-limiting example, polyethylene glycol (PEG) fatty aciddiesters. Illustrative and non-limiting examples of PEG-fatty aciddiesters are shown in Table 2.

TABLE 2 PEG-Fatty Acid Diester Surfactants COMPOUND COMMERCIAL PRODUCT(Supper) HLB PEG-4 dilaurate MAPEG ® 200 DL (PPG), 7 KESSCO ® PEG 200 DL(Stepan), LIPOPEG 6 2-DL (Lipo Chem.) PEG-4 dioleate MAPEG ® 200 DO(PPG), 6 PEG-4 distearate KESSCO ® 200 DS (Stepan) 5 PEG-6 dilaurateKESSCO ® PEG 300 DL (Stepan) 9.8 PEG-6 dioleate KESSCO ® PEG 300 DO(Stepan) 7.2 PEG-6 distearate KESSCO ® PEG 300 DS (Stepan) 6.5 PEG-8dilaurate MAPEG ® 400 DL (PPG), 11 KESSCO ® PEG 400 DL (Stepan), LIPOPEG4 DL (Lipo Chem.) PEG-8 dioleate MAPEG ® 400 DO (PPG), 8.8 KESSCO ® PEG400 DO (Stepan), LIPOPEG 4 DO (Lipo Chem.) PEG-8 distearate MAPEG ® 400DS (PPG), CDS 400 (Nikkol) 11 PEG-10 dipalmitate Polyaldo 2PKFG >10PEG-12 dilaurate KESSCO ® PEG 600 DL (Stepan) 11.7 PEG-12 distearateKESSCO ® PEG 600 DS (Stepan) 10.7 PEG-12 dioleate MAPEG ® 600 DO (PPG),10 KESSCO ® 600 DO (Stepan) PEG-20 dilaurate KESSCO ® PEG 1000 DL(Stepan) 15 PEG-20 dioleate KESSCO ® PEG 1000 DO (Stepan) 13 PEG-20distearate KESSCO ® PEG 1000 DS (Stepan) 12 PEG-32 dilaurate KESSCO ®PEG 1540 DL (Stepan) 16 PEG-32 dioleate KESSCO ® PEG 1540 DO (Stepan) 15PEG-32 distearate KESSCO ® PEG 1540 DS (Stepan) 15 PEG-400 dioleateCithrol 4DO series (Croda) >10 PEG-400 distearate Cithrol 4DS series(Croda) >10

As discussed above, in some embodiments, pharmaceutical compositionsdescribed herein comprise mixtures of surfactants, including, e.g.,mixtures of two or more commercial surfactant products Several PEG-fattyacid esters are marketed commercially as mixtures or mono- and diesters.Illustrative and non-limiting examples of surfactant mixtures are shownin Table 3.

TABLE 3 PEG-Fatty Acid Mono- and Diester Mixtures COMPOUND COMMERCIALPRODUCT (Supplier) HLB PEG 4-150 mono, KESSCO ® PEG 200-6000 mono,dilaurate dilaurate (Stepan) PEG 4-150 mono, KESSCO ® PEG 200-6000 mono,dioteate dioleate (Stepan) PEG 4-150 mono, KESSCO ® 200-6000 mono,distearate distearate (Stepan)

In some embodiments, surfactants described herein include, by way ofnon-limiting example, polyethylene glycol glycerol fatty acid esters(PEG glycerol fatty acid esters). Illustrative and non-limiting examplesof PEG glycerol fatty acid esters are shown in Table 4.

TABLE 4 PEG Glycerol Fatty Acid Esters COMPOUND COMMERCIAL PRODUCT(Supplier) HLB PEG-20 glyceryl laurate Tagat ® L (Goldschmidt) 16 PEG-30glyceryl laurate Tagat ® L2 (Goldschmidt) 16 PEG-15 glyceryl laurateGlycerox L series (Croda) 15 PEG-40 glyceryl laurate Glycerox L series(Croda) 15 PEG-20 glyceryl stearate Capmul ® EMG (ABITEC), 13 Aldo ®MS-20 KFG (Lonza) PEG-20 glyceryl oleate Tagat ® O (Goldschmidt) >10PEG-30 glyceryl oleate Tagat ® O2 (Goldschmidt) >10

In certain embodiments, surfactants of different degrees oflipophilicity or hydrophilicity are prepared by reaction of alcohols orpolyalcohols with a variety of natural and/or hydrogenated oils. In someembodiments, the oils used are castor oil or hydrogenated castor oil oran edible vegetable oil such as corn oil, olive oil, peanut oil, palmkernel oil, apricot kernel oil, or almond oil. In specific embodiments,alcohols include glycerol, propylene glycol, ethylene glycol,polyethylene glycol, sorbitol, and pentaerythritol. In certainembodiments, such surfactants are utilized in the pharmaceuticalcompositions described herein. Illustrative and non-limiting examples ofsurfactants of this class suitable for use in the pharmaceuticalcompositions described herein are shown in Table 5.

TABLE 5 Transesterification Products of Oils and Alcohols COMPOUNDCOMMERCIAL PRODUCT (Supplier) HLB PEG-3 castor oil Nikkol CO-3 (Nikko) 3PEG-5, 9, and 16 ACCONON CA series (ABITEC) 6-7 castor oil PEG-20 castoroil Emalex C-20 (Nihon Emulsion), 11 Nikkol CO-20 TX (Nikko) PEG-23castor oil Emulgante EL23 >10 PEG-30 castor oil Emalex C-30 (NihonEmulsion), 11 Alkamuls ® EL 620 (Rhone- Poulenc), lncrocas 30 (Croda)PEG-35 castor oil Cremophor EL and EL-P (BASF), Emulphor EL, Incrocas-35(Croda), Emulgin RO 35 (Henkel) PEG-38 castor oil Emulgante EL 65(Condea) PEG-40 castor oil Emalex C-40 (Nihon Emulsion), 13 Alkamuls ®EL 719 (Rhone- Poulenc) PEG-50 castor oil Emalex C-50 (Nihon Emulsion)14 PEG-56 castor oil Eumulgin ® PRT 56 (Pulcra SA) >10 PEG-60 castor oilNikkol CO-60TX (Nikko) 14 PEG-100 castor oil Thornley >10 PEG-200 castoroil Eumulgin ® PRT 200 (Pulcra SA) >10 PEG-5 hydrogenated Nikkol HCO-5(Nikko) 6 castor oil PEG-7 hydrogenated Simusol ® 989 (Seppic), 6 castoroil Cremophor WO7 (BASF) PEG-10 hydrogenated Nikkol HCO-10 (Nikko) 6.5castor oil PEG-20 hydrogenated Nikkol HCO-20 (Nikko) 11 castor oilPEG-25 hydrogenated Simulsol ® 1292 (Seppic), 11 castor oil Cerex ELS250 (Auschem SpA) PEG-30 hydrogenated Nikkol HCO-30 (Nikko) 11 castoroil PEG-40 hydrogenated Cremophor RH 40 (BASF), 13 castor oil Croduret(Croda), Emulgin HRE 40 (Henkel) PEG-45 hydrogenated Cerex ELS 450(Auschem Spa) 14 castor oil PEG-50 hydrogenated Emalex HC-50 (NihonEmulsion) 14 castor oil PEG-60 hydrogenated Nikkol HCO-60 (Nikko); 15castor oil Cremophor RH 60 (BASF) PEG-80 hydrogenated Nikkol HCO-80(Nikko) 15 castor oil PEG-100 Nikkol HCO-100 (Nikko) 17 hydrogenatedcastor oil PEG-6 corn oil Labrafil ® M 2125 CS (Gattefosse) 4 PEG-6almond oil Labrafil ® M 1966 CS (Gattefosse) 4 PEG-6 apricot Labrafil ®M 1944 CS (Gattefosse) 4 kernel oil PEG-6 olive oil Labrafil ® M 1980 CS(Gattefosse) 4 PEG-6 peanut oil Labrafil ® M 1969 CS (Gattefosse) 4PEG-6 hydrogenated Labrafil ® M 2130 BS (Gattefosse) 4 palm kernel oilPEG-6 palm kernel oil Labrafil ® M 2130 CS (Gattefosse) 4 PEG-6 trioleinLabrafil ® M 2735 CS (Gattefosse) 4 PEG-8 corn oil Labrafil ® WL 2609 BS(Gattefosse) 6-7 PEG-20 corn Crovol M40 (Croda) 10 glycerides PEG-20almond Crovol A40 (Croda) 10 glycerides PEG-25 trioleate TAGAT ® TO(Goldschmidt) 11 PEG-40 palm Crovol PK-70 >10 kernel oil PEG-60 cornCrovol M70 (Croda) 15 glycerides PEG-60 almond Crovol A70 (Croda) 15glycerides PEG-4 caprylic/capric Labrafac ® Hydro (Gattefosse), 4-5triglyceride PEG-8 caprylic/capric Labrasol (Gattefosse), >10 glyceridesLabrafac CM 10 (Gattefosse) PEG-6 caprylic/capric SOFTIGEN ® 767 (Huls),19 glycerides Glycerox 767 (Croda) Lauroyl macrogol-32 GELUCIRE 44/14(Gattefosse) 14 glyceride Stearoyl macrogol GELUCIRE 50/13 (Gattefosse)13 glyceride Mono, di, tri, tetra SorbitoGlyceride (Gattefosse) <10esters of vegetable oils and sorbitol Pentaerythrityl Crodamol PTIS(Croda) <10 tetraisostearate Pentaerythrityl Albunol DS (Taiwan Surf.)<10 distearate Pentaerythrityl Liponate PO-4 (Lipo Chem.) <10tetraoleate Pentaerythrityl Liponate PS-4 (Lipo Chem.) <10 tetrastearatePentaerythrityl Liponate PE-810 (Lipo Chem.), <10 tetracaprylate/Crodamol PTC (Croda) tetracaprate Pentaerythrityl Nikkol Pentarate 408(Nikko) tetraoctanoate

In some embodiments, surfactants utilized in the pharmaceuticalcompositions described herein include, by way of non-limiting example,polyglycerized fatty acids. Illustrative and non-limiting examples ofsuitable polyglyceryl esters are shown in Table 6.

TABLE 6 Polyglycerized Fatty Acids COMMERCIAL PRODUCT COMPOUND(Supplier) HLB Polyglyceryl-2 stearate Nikkol DGMS (Nikko) 5-7 Polyglyceryl-2 oleate Nikkol DGMO (Nikko) 5-7  Polyglyceryl-2isostearate Nikkol DGMIS (Nikko) 5-7  Polyglyceryl-3 oleate CAPROL ® 3G0(ABITEC), 6.5 Drewpol 3-1-O (Stepan) Polyglyceryl-4 oleate NikkolTetraglyn 1-O (Nikko) 5-7  Polyglyceryl-4 stearate Nikkol Tetraglyn 1-S(Nikko) 5-6  Polyglyceryl-6 oleate Drewpol 6-1-O (Stepan), 9 NikkolHexaglyn 1-O (Nikko) Polyglyceryl-10 laurate Nikkol Decaglyn 1-L (Nikko)15 Polyglyceryl-10 oleate Nikkol Decaglyn 1-O (Nikko) 14 Polyglyceryl-10stearate Nikkol Decaglyn 1-S (Nikko) 12 Polyglyceryl-6 ricinoleateNikkol Hexaglyn PR-15 (Nikko) Polyglyceryl-10 linoleate Nikkol DecaglynI-LN (Nikko) 12 Polyglyceryl-6 pentaoleate Nikkol Hexaglyn S—O (Nikko)<10 Polyglyceryl-3 dioleate Cremophor G032 (BASF) <10 Polyglyceryl-3distearate Cremophor GS32 (BASF) <10 Polyglyceryl-4 pentaoleate NikkolTetraglyn 5-O (Nikko) <10 Polyglyceryl-6 dioleate CAPROL ® 6G20 8.5(ABITEC); Hodag PGO-62 (Calgene), PLUROL OLEIQUE CC 497 (Gattefosse)Polyglyceryl-2 dioleate Nikkol DGDO (Nikko) 7 Polyglyceryl-10 trioleateNikkol Decaglyn 3-O (Nikko) 7 Polyglyceryl-10 pentaoleate NikkolDecaglyn 5-O (Nikko) 3.5 Polyglyceryl-10 septaoleate Nikkol Decagtyn 7-O(Nikko) 3 Polyglyceryl-10 tetraoleate CAPROL ® 10G40 (ABITEC); 6.2 HodagPGO-62 (CALGENE), Drewpol 10-4-O (Stepan) Polyglyceryl-10decaisostearate Nikkol Decaglyn 10-IS (Nikko) <10 Polyglyceryl-10decaoleate Drewpol 10-10-O (Stepan), 3.5 CAPROL 10G10O (ABITEC), NikkolDecaglyn 10-O Polyglyceryl-10 mono, CAPROL ® PGE 860 (ABITEC) 11dioleate Polyglyceryl polyricinoleate Polymuls (Henkel) 3-20

In some embodiments, surfactants utilized in the pharmaceuticalcompositions described herein include, by way of non-limiting exampleesters of propylene glycol and fatty acids. Illustrative andnon-limiting examples of surfactants of this class are given in Table 7.

TABLE 7 Propylene Glycol Fatty Acid Esters COMMERCIAL PRODUCT COMPOUND(Supplier) HLB Propylene glycol monocaprylate Capryol 90 (Gattefosse),<10 Nikkol Sefsol 218 (Nikko) Propylene glycol monolaurate Lauroglycol90 (Gattefosse), <10 Lauroglycol FCC (Gattefosse) Propylene glycololeate Lutrol OP2000 (BASF) <10 Propylene glycol myristate Mirpyl <10Propylene glycol monostearate ADM PGME-03 (ADM), 3-4 LIPO PGMS (LipoChem.), Aldo ® PGHMS (Lonza) Propylene glycol hydroxy <10 stearatePropylene glycol ricinoleate PROPYMULS (Henkel) <10 Propylene glycolisostearate <10 Propylene glycol monooleate Myverol P-06 (Eastman) <10Propylene glycol Captex ® >6 dicaprylate/dicaprate 200 (ABITEC),Miglyol ® 840 (Huls), Neobee ® M-20 (Stepan) Propylene glycoldioctanoate Captex ® 800 (ABITEC) Propylene glycol LABRAFAC >6caprylate/caprate PG (Gattefosse) Propylene glycol dilaurate >6Propylene glycol distearate KESSCO ® PGDS (Stepan) >6 Propylene glycoldicaprylate Nikkol Sefsol 228 (Nikko) >6 Propylene glycol dicaprateNikkol PDD (Nikko) >6

As discussed above, mixtures of surfactants are also used, in someembodiments, in the pharmaceutical compositions described herein.Mixtures of surfactants include, by way of non-limiting example,mixtures of propylene glycol fatty acid esters and glycerol fatty acidesters are suitable and are commercially available, Illustrative andnon-limiting examples of such mixtures of surfactants include, by way ofnon-limiting example, those shown in Table 8.

TABLE 8 Glycerol/Propylene Glycol Fatty Acid Esters COMMERCIAL PRODUCTCOMPOUND (Supplier) HLB Oleic ATMOS 300; ARLACEL 186 (ICI) 3-4 StearicATMOS 150 3-4

In certain embodiments, an important class of surfactants includes theclass of mono- and diglycerides. These surfactants are generallylipophilic. Illustrative and non-limiting examples of these surfactantsare given in Table 9.

TABLE 9 Mono- and Diglyceride Surfactants COMMERCIAL PRODUCT COMPOUND(Supplier) HLB Monopalmitolein (C16:1) (Larodan) <10 Monoelaidin (C18:1)(Larodan) <10 Monocaproin (C6) (Larodan) <10 Monocaprylin (Larodan) <10Monocaprin (Larodan) <10 Monolaurin (Larodan) <10 Glyceryl Nikkol MGM(Nikko) 3-4 monomyristate (C14) Glyceryl monooleate PECEOL (Gattefosse),3-4 (C18:1) Hodag GMO-D, Nikkol MGO (Nikko) Glyceryl monooleate RYLOseries (Danisco), 3-4 DIMODAN series (Danisco), EMULDAN (Danisco),ALDO ® MO FG (Lonza), KESSCO GMO (Stepan), MONOMULS ® series (Henkel),TEGIN O, DREWMULSE GMO (Stepan), Atlas G-695 (ICI), GMOrphic 80(Eastman), ADM DMG-40, 70, and 100 (ADM), Myverol (Eastman) Glycerolmonooleate/ OLICINE (Gattefosse) 3-4 linoleate Glycerol monolinoleateMaisine (Gattefosse), 3-4 MYVEROL 18-92, Myverol 18-06 (Eastman)Glyceryl Softigen ® 701 (Huls), 6 ricinoleate HODAG GMR-D (Calgene),ALDO ® MR (Lonza) Glyceryl ALDO ® MLD (Lonza), 6.8 monolaurate Hodag GML(Calgene) Glycerol monopalmitate Emalex GMS-P (Nihon) 4 GlycerolCapmul ® GMS. (ABITEC), 5-9 monostearate Myvaplex (Eastman), IMWITOR ®191 (Hüls), CUTINA GMS, Aldo ® MS (Lonza), Nikkol MGS series (Nikko)Glyceryl Capmul ® GMO-K (ABITEC) <10 mono-, dioleate Glyceryl CUTINAMD-A, ESTAGEL-G18 <10 palmitic/stearic Glyceryl acetate Lamegin ® EE(Grünau GmbH) <10 Glycery laurate Inwitor ® 312 (Hüls), 4 Monomuls ®90-45 (Grünau GmbH), Ado ® MLD (Lonza) Glycely citrate/ Imwitor ® 375(Hüls) <10 lactate/oleate/linoleate Glyceryl caprylate lmwitor ® 308(Hüls), 5-6 Capmul ® MCMC8 (ABITEC) Glyceryl Capmul ® MCM (ABITEC) 5-6caprylate/caprate Caprylic acid mono, Imwitor ® 988 (Hüls) 5-6diglycerides Caprylic/capric Imwitor ® 742 (Hüls) <10 glyceridesMono-and diacetylated Myvacet ® 9-45, 3.8-4 monoglycerides Myvacet ®9-40, Myvacet ® 9-08 (Eastman), Lamegin ® (Grünau) Glyceryl monostearateAldo ® MS, Arlacel 129 (ICI), 4.4 LIPO GMS (Lipo Chem.), Imwitor ® 191(Hüls), Myvaplex (Eastman) Lactic acid esters of LAMEGIN GLP (Henkel)<10 mono, diglycerides Dicaproin (C6) (Larodan) <10 Dicaprin (C10)(Larodan) <10 Dioctanoin (C8) (Larodan) <10 Dimyristin (C14) (Larodan)<10 Dipalmitin (C16) (Larodan) Distearin (Larodan) <10 Glyceryldilaurate (C12) Caomul ® GDL (ABITEC) 3-4 Glyceryl dioleate Caprnul ®GDO (ABITEC) 3-4 Glycerol esters of GELUCIRE 39/01 (Gattefosse), 1 fattyacids GELUCIRE 43/01 (Gattefosse) 6 GELUCIRE 37/06 (Gattefosse)Dipalmitolein (C16:1) (Larodan) 1,2 and 1,3-diolein (C18:1) (Larodan)<10 Dielaidin (C18:1) (Larodan) <10 Dilinolein (C18:2) (Larodan) <10

In some embodiments, surfactants utilized in the pharmaceuticalcompositions described herein include sterols and derivatives ofsterols. In various embodiments, these surfactants are hydrophilic orlipophilic. Illustrative and non-limiting examples of surfactants ofthis class are shown in Table 10.

TABLE 10 Sterol and Sterol Derivative Surfactants COMMERCIAL PRODUCTCOMPOUND (Supplier) HLB Cholesterol, sitosterol, <10 lanosterol PEG-24cholesterol ether Solulan C-24 (Amerchol) >10 PEG-30 cholestanol NikkolDHC (Nikko) >10 Phytosterol GENEROL series (Henkel) <10 PEG-25 phytosterol Nikkol BPSH-25 (Nikko) >10 PEG-5 soya sterol Nikkol BPS-S (Nikko)<10 PEG-10 soya sterol Nikkol BPS-10 (Nikko) <10 PEG-20 soya sterolNikkol BPS-20 (Nikko) <10 PEG-30 soya sterol Nikkol BPS-30 (Nikko) >10

In some embodiments, surfactants useful in the pharmaceuticalcompositions described herein include a variety of PEG-sorbitan fattyacid esters. In general, these surfactants are hydrophilic, althoughseveral lipophilic surfactants of this class can be used. Illustrativeand non-limiting examples of these surfactants are shown in Table 11.

TABLE 11 PEG-Sorbitan Fatty Acid Esters COMMERCIAL PRODUCT COMPOUND(Supplier) HLB PEG-10 sorbitan laurate Liposorb L-10 (Lipo Chem.) >10PEG-20 sorbitan monolaurate Tween-20 (Atlas/ICI), 17 Crillet 1 (Croda),DACOL MLS 20 (Condea) PEG-4 sorbitan monolaurate Tween-21 (Atlas/ICI),13 Crillet 11 (Croda) PEG-80 sorbitan monolaurate Hodag PSML-80(Calgene): >10 T-Maz 28 PEG-6 sorbitan monolaurate Nikkol GL-1 (Nikko)16 PEG-20 sorbitan monopalmitate Tween-40 (Atlas/ICI); 16 Crillet 2(Croda) PEG-20 sorbitan monostearate Tween-60 (Atlas/ICI), 15 Crillet 3(Croda) PEG-4 sorbitan monostearate Tween-61 (Atlas/ICI), 9.6 Crillet 31(Croda) PEG-8 sorbitan monostearate DACOL MSS (Condea) >10 PBG-6sorbitan monostearate Nikkol TS106 (Nikko) 11 PEG-20 sorbitantristearate Tween-65 (Atlas/ICI), 11 Crillet 35 (Croda) PEG-6 sorbitantetrastearate Nikkol GS-6 (Nikko) 3 PEG-60 sorbitan tetrastearate NikkolGS-460 (Nikko) 13 PEG-5 sorbitan monooleate Tween-81 (Atlas/ICI), 10Crillet 41 (Croda) PEG-6 sorbitan monooleate Nikkol TO-106 (Nikko) 10PEG-20 sorbitan monooleate Tween-80 (Atlas/ICI), 15 Crillet 4 (Croda)PEG-40 sorbitan oleate Emalex ET 8040 18 (Nihon Emulsion) PEG-20sorbitan trioleate Tween-85 (Atlas/ICI), 11 Crillet 45 (Croda) PEG-6sorbitan tetraoleate Nikkol GO-4 (Nikko) 8.5 PEG-30 sorbitan tetraoleateNikkol GO-430 (Nikko) 12 PEG-40 sorbitan tetraoleate Nikkol GO-440(Nikko) 13 PEG-20 sorbitan Tween-120 (Atlas/ICI), >10 monoisostearateCrillet 6 (Croda) PEG sorbitol hexaoleate Atlas G-1086 (ICI) 10 PEG-6sorbitol hexastearate Nikkol GS-6 (Nikko) 3

In some embodiments, surfactants utilized herein include ethers ofpolyethylene glycol and alkyl alcohols Illustrative and non-limitingexamples of these surfactants are shown in Table 12.

TABLE 12 Polyethylene Glycol Alkyl Ethers COMMERCIAL PRODUCT COMPOUND(Supplier) HLB PEG-2 oleyl ether, oleth-2 Brij 92/93 (Atlas/ICI) 4.9PEG-3 oleyl ether, oleth-3 Volpe 3 (Croda) <10 PEG-5 oleyl ether,oleth-5 Volpe 5 (Croda) <10 PEG-10 oleyl ether, oleth-10 Volpe 10(Croda), 12 Brij 96/97 (Atlas/ICI) PEG-20 oleyl ether, oleth-20 Volpo 20(Croda), 15 Brij 93/99 (Atlas/ICI) PEG-4 lauryl ether, laureth-4 Brij 30(Atlas/ICI) 9.7 PEG-9 lauryl ether >10 PEG-23 lauryl ether, laureth-23Brij 35 (Atlas/ICI) 17 PEG-2 cetyl ether Brij 52 (ICI) 5.3 PEG-10 cetylether Brij 56 (ICI) 13 PEG-20 cetyl ether Brij 58 (ICI) 16 PEG-2 stearylether Brij 72 (ICI) 4.9 PEG-10 stearyl ether Brij 76 (ICI) 12 PEG-20stearyl ether Brij 73 (ICI) 15 PEG-100 stearyl ether Brij 700 (ICI) >10

In certain embodiments, surfactants utilized in the pharmaceuticalcompositions described herein include esters of sugars. Illustrative andnon-limiting examples of such surfactants are shown in Table 13.

TABLE 13 Sugar Ester Surfactants COMPOUND COMMERCIAL PRODUCT (Supper)HLB Sucrose distearate SUCRO ESTER 7 (Gattefosse), 3 Crodesta F-10(Croda) Sucrose distearate/ SUCRO ESTER 11 (Gattefosse), 12 monostearateCrodesta F-110 (Croda) Sucrose dipalmitate 7.4 Sucrose monostearateCrodesta F-160 (Croda) 15 Sucrose monopalmitate SUCRO ESTER 15(Gattefosse) >10 Sucrose monolaurate Saccharose monolaurate 15 1695(Mitsubishi-Kasei)

In some embodiments, surfactants utilized in the pharmaceuticalcompositions described herein include polyethylene glycol alkyl phenols,e.g., hydrophilic PEG-alkyl phenol surfactants Illustrative andnon-limiting examples of these surfactants are shown in Table 14.

TABLE 14 Polyethylene Glycol Alkyl Phenol Surfactants COMPOUNDCOMMERCIAL PRODUCT (Supplier) HLB PEG-10-100 Triton X series (Rohm &Haas), >10 nonyl pheno Igepal CA series (GAF, USA), Antarox CA series(GAF, UK) PEG-15-100 Triton N-series (Rohm & Haas), >10 octyl phenolether Igepal CO series (GAF, USA), Antarox CO series (GAF, UK)

In certain embodiments, surfactants utilized in pharmaceuticalcompositions described herein include polyoxyethylene-polyoxypropyleneblock copolymers. POE-POP block copolymers are a unique class ofpolymeric surfactants. The unique structure of the surfactants, withhydrophilic POE and lipophilic POP moieties in well-defined ratios andpositions, provides a wide variety of surfactants suitable for use inthe present invention. These surfactants are available under varioustrade names, including Synperonic PE series (ICI); Pluronic® series(BASF), Emkalyx, Lutrol (BASF), Supronic, Monolan, Pluracare, andPlurodac. The generic term for these polymers is “poloxamer” (CAS9003-11-6). These polymers have the formula:HO(C₂H₄O)_(a)(C₃H₆O)_(b)(C₂H₄O)_(a)H; wherein the terms “a” and “b”denote the number of polyoxyethylene and polyoxypropylene units,respectively.

Illustrative and non-limiting examples of suitable surfactants of thisclass are shown in Table 15. Since the compounds are widely available,commercial sources are not listed in the Table. The compounds are listedby generic name, with the corresponding “a” and “b” values.

TABLE 15 POE-POP Block Copolymers a, b values in COMPOUNDHO(C₂H₄O)_(a)(C₃H₆O)_(b)(C₂H₄O)₃H HLB Poloxamer 105 a = 11; b = 16 8Poloxamer 108 a = 46; b = 16 >10 Poloxamer 122 a = 5; b = 21 3 Poloxamer123 a = 7; b = 21 7 Poloxamer 124 a = 11; b = 21 >7 Poloxamer 181 a = 3;b = 30 Poloxamer 182 a = 8; b = 30 2 Poloxamer 183 a = 10; b = 30Poloxamer 184 a = 13; b = 30 Poloxamer 185 a = 19; b = 30 Poloxamer 188a = 75; b = 30 29 Poloxamer 212 a = 8; b = 35 Poloxamer 215 a = 24; b =35 Poloxamer 217 a = 52; b = 35 Poloxamer 231 a = 16; b = 39 Poloxamer234 a = 22; b = 39 Poloxamer 235 a = 27; b = 39 Poloxamer 237 a = 62; b= 39 24 Poloxamer 238 a = 97; b = 39 Poloxamer 282 a = 10; b = 47Poloxamer 284 a = 21; b = 47 Poloxamer 288 a = 122; b = 47 >10 Poloxamer331 a = 7; b = 54 0.5 Poloxamer 333 a = 20; b = 54 Poloxamer 334 a = 31;b = 54 Poloxamer 335 a = 38; b = 54 Poloxamer 338 a = 128; b = 54Poloxamer 401 a = 6; b = 67 Poloxamer 402 a = 13; b = 67 Poloxamer 403 a= 21; b = 67 Poloxamer 407 a = 98; b = 67

In some embodiments, surfactants utilized in pharmaceutical compositionsdescribed herein include sorbitan esters of fatty acids Illustrative andnon-limiting examples of such surfactants are shown in Table 16.

TABLE 16 Sorbitan Fatty Acid Ester Surfactants COMPOUND COMMERCIALPRODUCT (Supplier) HLB Sorbitan monolaurate Span-20 (Atlas/ICI), Crill 1(Croda), 8.6 Arlacel 20 (ICI) Sorbitan monopalmitate Span-40(Atlas/ICI), Crill 2 (Croda), 6,7 Nikkol SP-10 (Nikko) Sorbitanmonooleate Span-80 (Atlas/ICI), Crill 4 (Croda), 4.3 Crill 50 (Croda)Sorbitan monostearate Span-60 (Atlas/ICI), Crill 3 (Croda), 4.7 NikkolSS-10 (Nikko) Sorbitan trioleate Span-85 (Atlas/ICI), Crill 45 (Croda),4.3 Nikkol SO-30 (Nikko) Sorbitan sesquioleate Arlacel-C (ICI), Crill 43(Croda), 3.7 Nikkol SO-15 (Nikko) Sorbitan tristearate Span-65(Atlas/ICI) Crill 35 (Croda), 2.1 Nikkol SS-30 (Nikko) Sorbitanmonoisostearate Crill 6 (Croda), Nikkol SI-10 (Nikko) 4.7 Sorbitansesquistearate Nikkol SS-15 (Nikko) 4.2

In certain embodiments, surfactants utilized in pharmaceuticalcompositions described herein include esters of lower alcohols (C₂ toC₄) and fatty acids (C₈ to C₁₈). Illustrative and non-limiting examplesof these surfactants are shown in Table 17.

TABLE 17 Lower Alcohol Fatty Acid Ester Surfactants COMPOUND COMMERCIALPRODUCT (Supplier) HLB Ethyl oleate Crodamol EO (Croda), <10 Nikkol EOO(Nikko) Isopropyl myristate Crodamol IPM (Croda) <10 Isopropyl palmitateCrodamol IPP (Croda) <10 Ethyl linoleate Nikkol VF-E (Nikko) <10Isopropyl linoleate Nikkol VF-IP (Nikko) <10

In some embodiments, hydrophilic surfactants utilized in pharmaceuticalcompositions described herein include ionic surfactants (e.g., cationic,anionic and zwitterionic surfactants). In specific embodiments, anionicsurfactants include fatty acid salts and bile acid salts. In certainspecific embodiments, cationic surfactants include carnitines. In somespecific embodiments, ionic surfactants include, by way of non-limitingexample, sodium oleate, sodium lauryl sulfate, sodium laurylsarcosinate, sodium dioctyl sulfosuccinate, sodium cholate, sodiumtaurocholate lauroyl carnitine palmitoyl carnitine and myristoylcarnitine Illustrative and non-limiting examples of such surfactants areshown in Table 18. For simplicity, exemplary counterions are shown inthe entries in the Table. In various embodiments, such counterions areoptionally substituted with any suitable counterion. For example,although the fatty acids are shown as sodium salts, other cationcounterions are optionally used, such as alkali metal cations orammonium. Unlike certain non-ionic surfactants, these ionic surfactantsare generally available as pure compounds, rather than commercial(proprietary) mixtures. Because these compounds are readily availablefrom a variety of commercial suppliers, such as Aldrich, Sigma, and thelike, commercial sources are not generally listed in the Table.

TABLE 18 Ionic Surfactants COMPOUND HLB FATTY ACID SALTS >10 Sodiumcaproate Sodium caprylate Sodium caprate Sodium laurate Sodium myristateSodium myristolate Sodium palmitate Sodium palmitoleate Sodium oleate 18Sodium ricinoleate Sodium linoleate Sodium linolenate Sodium stearateSodium lauryl sulfate (dodecyl) 40 Sodium tetradecyl sulfate Sodiumlauryl sarcosinate Sodium dioctyl sulfosuccinate [sodium docusate(Cytec)] BILE SALTS >10 Sodium cholate Sodium taurocholate Sodiumglycocholate Sodium deoxycholate Sodium taurodeoxycholate Sodiumglycodeoxycholate Sodium ursodeoxycholate Sodium chenodeoxycholateSodium taurochenodeoxycholate Sodium glyco cheno deoxycholate Sodiumcholylsarcosinate Sodium N-methyl taurocholate Sodium lithocholatePHOSPHOLIPIDS Egg/Soy lecithin [Epikuron ™ (Lucas Meyer), Ovothin ™(Lucas Meyer)] Lyso egg/soy lecithin Hydroxylated lecithinLysophosphatidylcholine Cardiolipin Sphingomyelin PhosphatidylcholinePhosphatidyl ethanolamine Phosphatidic acid Phosphatidyl glycerolPhosphatidyl serine PHOSPHORIC ACID ESTERS Diethanolammoniumpolyoxyethylene-10 oleyl ether phosphate Esterification products offatty alcohols or fatty alcohol ethoxylates with phosphoric acid oranhydride CARBOXYLATES Ether carboxylates (by oxidation of terminal OHgroup of fatty alcohol ethoxylates) Succinylated monoglycerides [LAMEGINZE (Henkel)] Sodium stearyl fumarate Stearoyl propylene glycol hydrogensuccinate Mono/diacetylated tartaric acid esters of mono- anddiglycerides Citric acid esters of mono-, diglycerides Glyceryl-lactoesters of fatty acids (CFR ref. 172.852) Acyl lactylates: lactylicesters of fatty acids calcium/sodium stearoyl-2-lactylate calcium/sodiumstearoyl lactylate Alginate salts Propylene glycol alginate SULFATES ANDSULFONATES Ethoxylated alkyl sulfates Alkyl benzene sulfones α-olefinsulfonates Acyl isethionates Acyl taurates Alkyl glyceryl ethersulfonates Octyl sulfosuccinate disodium Disodiumundecylenamideo-MEA-sulfosuccinate CATIONIC Surfactants >10 Lauroylcarnitine Palmitoyl camitine Myristoyl carnitine Hexadecyl triammoniumbromide Decyl trimethyl ammonium bromide Cetyl trimethyl ammoniumbromide Dodecyl ammonium chloride Alkyl benzyldimethylammonium saltsDiisobutyl phenoxyethoxydimethyl benzylammonium salts Alkylpyridiniumsalts Betaines (trialkylglycine): Lauryl betaine (N-lauryl,N,N-dimethylglycine) Ethoxylated amines: Polyoxyethylene-15 coconutamine

In some embodiments, surfactants utilized in pharmaceutical compositionsdescribed herein include ionizable surfactants. In certain embodiments,ionizable surfactants, when present in their unionized (neutral,non-salt) form, are lipophilic surfactants suitable for use in thecompositions of the present invention Particular examples of suchsurfactants include free fatty acids, particularly C₆-C₂₂ fatty acids,and bile acids. More specifically, suitable unionized ionizablesurfactants include the free fatty acid and bile acid forms of any ofthe fatty acid salts and bile salts shown in Table 18.

In some instances, derivatives of oil-soluble vitamins, such as vitaminsA, D, E, K, etc., are also useful surfactants for use in thepharmaceutical compositions described herein. An example of such aderivative is tocopheryl PEG-1000 succinate (TPGS, available fromEastman).

In specific embodiments, surfactants or mixtures of surfactants thatsolidify (e.g., form a solid, a semi-solid, a gel, a jelly, a paste, orthe like) at ambient room temperature are utilized in the pharmaceuticalcompositions described herein. In certain specific embodiments,surfactants or mixtures of surfactants utilized in the pharmaceuticalcompositions described herein solidify (e.g., form a solid, asemi-solid, a gel, a jelly, a paste, or the like) at ambient roomtemperature when combined with additional agents (e.g., particularlipophilic components, such as triglycerides, vitamins (e.g., VitaminE), or the like, viscosity modifiers, stabilizers, solidifying agents,binders, thickeners, or the like). Such additional agents are optionallyutilized in the pharmaceutical compositions described herein. In certainembodiments, pharmaceutical compositions described herein comprise ahydrophilic carrier (e.g., a hydrophilic surfactant), a lipophiliccarrier, and/or a viscosity modifier or solidifying agent.

In some specific embodiments, non-ionic hydrophilic surfactants includealkylglucosides, alkylmaltosides; alkylthioglucosides; laurylmacrogolglycerides, polyoxyethylene alkyl ethers; polyoxyethylenealkylphenols; polyethylene glycol fatty acids esters; polyethyleneglycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acidesters; polyoxyethylene-polyoxypropylene block copolymers; polyglycerolfatty acid esters; polyoxyethylene glycerides, polyoxyethylene sterols,derivatives, and analogues thereof, polyoxyethylene vegetable oils;polyoxyethylene hydrogenated vegetable oils; reaction mixtures ofpolyols with fatty acids, glycerides, vegetable oils, hydrogenatedvegetable oils, and sterols; sugar esters, sugar ethers;sucroglycerides; polyethoxylated fat-soluble vitamins or derivatives;and mixtures thereof.

In certain specific embodiments, the non-ionic hydrophilic surfactant isselected from, by way of non-limiting example, polyoxyethylenealkylethers; polyethylene glycol fatty acids esters, polyethylene glycolglycerol fatty acid esters, polyoxyethylene sorbitan fatty acid esters;polyoxyethylene-polyoxypropylene block copolymers; polyglyceryl fattyacid esters; polyoxyethylene glycerides; polyoxyethylene vegetable oils;and polyoxyethylene hydrogenated vegetable oils. In various embodiments,the glyceride is a monoglyceride, diglyceride, triglyceride, or amixture thereof.

In some specific embodiments, non-ionic hydrophilic surfactants are theproducts of reaction mixtures of polyols and fatty acids, glycerides,vegetable oils, hydrogenated vegetable oils or sterols. These reactionmixtures are largely composed of the transesterification products of thereaction, along with often complex mixtures of other reaction products.In more specific embodiments, the polyol is glycerol, ethylene glycol,polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or asaccharide.

In certain specific embodiments, the hydrophilic surfactant is orincludes an ionic surfactant. Specific ionic surfactants include alkylammonium salts; bile acids and salts, analogues, and derivativesthereof, fusidic acid and derivatives thereof; fatty acid derivatives ofamino acids, oligopeptides, and polypeptides: glyceride derivatives ofamino acids, oligopeptides, and polypeptides; acyl lactylates;mono-,diacetylated tartaric acid esters of mono-,diglycerides;succinylated monoglycerides; citric acid esters of mono-,diglycerides;alginate salts; propylene glycol alginate; lecithins and hydrogenatedlecithins; lysolecithin and hydrogenated lysolecithins;lysophospholipids and derivatives thereof; phospholipids and derivativesthereof; salts of alkylsulfates, salts of fatty acids; sodium docusate;carnitines; and mixtures thereof.

In some specific embodiments, ionic surfactants include bile acids andsalts, analogues, and derivatives thereof; lecithins, lysolecithin,phospholipids, lysophospholipids and derivatives thereof: salts ofalkylsulfates; salts of fatty acids; sodium docusate; acyl lactylates;mono-,diacetylated tartaric acid esters of mono-,diglycerides;succinylated monoglycerides; citric acid esters of mono-diglycerides;carnitines; and mixtures thereof. In more specific embodiments, ionicsurfactants include, by way of non-limiting example, lecithin,lysolecithin, phosphatidylcholine, phosphatidylethanolamine,phosphatidylglycerol, phosphatidic acid, phosphatidylserine,lysophosphatidylcholine, lysophosphatidylethanolamine,lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine,PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactylicesters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate,succinylated monoglycerides, mono/diacetylated tartaric acid esters ofmono/diglycerides, citric acid esters of mono/diglycerides, cholate,taurocholate, glycocholate, deoxycholate, taurodeoxycholate,chenodeoxycholate, glycodeoxycholate, glycochenodeoxycholate,taurochenodeoxycholate, ursodeoxycholate, tauroursodeoxycholate,glycoursodeoxycholate, cholylsarcosine, N-methyl taurocholate, caproate,caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate,linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate,docusate, lauroyl carnitines, palmitoyl carnitines, myristoyl camitines,and salts and mixtures thereof. In more specific embodiments, ionicsurfactants are selected from lecithin, lysolecithin,phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol,lysophosphatidylcholine, PEG-phosphatidylethanolamine, lactylic estersof fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylatedmonoglycerides, mono/diacetylated tartaric acid esters ofmonodiglycerides, citric acid esters of mono/diglycerides, cholate,taurocholate, glycocholate, deoxycholate, taurodeoxycholate,glycodeoxycholate, cholylsarcosine, caproate, caprylate, caprate,laurate, oleate, lauryl sulfate, docusate, and salts and mixturesthereof, with the most preferred ionic surfactants being lecithin,lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyllactylate, succinylated monoglycerides, mono/diacetylated tartaric acidesters of mono/diglycerides, citric acid esters of mono/diglycerides,taurocholate, caprylate, caprate, oleate, lauryl sulfate, docusate, andsalts and mixtures thereof.

In various embodiments, lipophilic surfactants are selected from, by wayof non-limiting example, alcohols; polyoxyethylene alkylethers; fattyacids; glycerol fatty acid esters; acetylated glycerol fatty acidesters; lower alcohol fatty acids esters; polyethylene glycol fattyacids esters; polyethylene glycol glycerol fatty acid esters;polypropylene glycol fatty acid esters; polyoxyethylene glycerides,lactic acid derivatives of mono/diglycerides; propylene glycoldiglycerides; sorbitan fatty acid esters; polyoxyethylene sorbitan fattyacid esters; polyoxyethylene-polyoxypropylene block copolymers;transesterified vegetable oils: sterols, sterol derivatives; sugaresters: sugar ethers; sucroglycerides: polyoxyethylene vegetable oils;and polyoxyethylene hydrogenated vegetable oils. As with the hydrophilicsurfactants, lipophilic surfactants are optionally the products ofreaction mixtures of polyols and fatty acids, glycerides, vegetableoils, hydrogenated vegetable oils, and sterols. In specific embodiments,lipophilic surfactants are selected from fatty acids; lower alcoholfatty acid esters; polyethylene glycol glycerol fatty acid esters;polypropylene glycol fatty acid esters; polyoxyethylene glycerides;glycerol fatty acid esters; acetylated glycerol fatty acid esters;lactic acid derivatives of mono/diglycerides; sorbitan fatty acidesters: polyoxyethylene sorbitan fatty acid esters;polyoxyethylene-polyoxypropylene block copolymers; polyoxyethylenevegetable oils, polyoxyethylene hydrogenated vegetable oils; andreaction mixtures of polyols and fatty acids, glycerides, vegetableoils, hydrogenated vegetable oils, and sterols. In certain specificembodiments, lipophilic surfactants are selected from lower alcoholfatty acids esters; polypropylene glycol fatty acid esters; propyleneglycol fatty acid esters: glycerol fatty acid esters; acetylatedglycerol fatty acid esters; lactic acid derivatives ofmono/diglycerides, sorbitan fatty acid esters; polyoxyethylene vegetableoils; and mixtures thereof, with glycerol fatty acid esters andacetylated glycerol fatty acid esters being most preferred. Among theglycerol fatty acid esters, the esters are, e.g., mono- or diglycerides,or mixtures of mono- and diglycerides, where the fatty acid moiety is aC₆ to C₂₂ fatty acid. In some specific embodiments, lipophilicsurfactants are selected from the products of reaction mixture ofpolyols and fatty acids, glycerides, vegetable oils, hydrogenatedvegetable oils, and sterols. In more specific embodiments, polyols arepolyethylene glycol, sorbitol, propylene glycol, and pentaerythritol.

In certain embodiments, pharmaceutical compositions described hereininclude a lipophilic component or carrier. In some embodiments, thelipophilic carrier is selected from lipophilic surfactants,triglycerides, and Vitamin E compounds (e.g., d,l-α-tocopherol). Inspecific embodiments, triglycerides utilized in the pharmaceuticalcompositions described herein are those that solidify (e.g., form asolid, a semi-solid, a gel, a jelly, a paste, or the like) at ambientroom temperature, with or without addition of appropriate additives, orthose which in combination with particular surfactants and/or activeingredients solidify at room temperature. Illustrativeandnon-limitingexamplesoftriglyceridessuitableforuseinthepharmaceuticalcompositions described herein are shown in Table 19. In general, thesetriglycerides are readily available from commercial sources. For severaltriglycerides, representative commercial products and/or commercialsuppliers are listed.

TABLE 19 Triglycerides Triglyceride Commercial Source Aceituno oilAlmond oil Super Refined Almond Oil (Croda) Araehis oil Babassu oilBeeswax Blackcurrant seed oil Borage oil Buffalo ground oil Candlenutoil Canola oil Lipex 108 (Abitec) Castor oil Chinese vegetable tallowoil Cocoa butter Coconut oil Pureco 76 (Abitec) Coffee seed oil Corn oilSuper Refined Corn Oil (Croda) Cottonseed oil Super Refined CottonseedOil (Croda) Crambe oil Cuphea species oil Evening primrose oil Grapeseedoil Groundnut oil Hemp seed oil Illpe butter Kapok seed oil Linseed oilMenhaden oil Super Refined Menhaden Oil (Croda) Mowrah butter Mustardseed oil Oiticica oil Olive oil Super Refined Olive Oil (Croda) Palm oilPalm kernel oil Peanut oil Super Refined Peanut Oil (Croda) Poppy seedoil Rapeseed oil Rice bran oil Safflower oil Super Refined Safflower Oil(Croda) Sal fat Sesame oil Super Refined Sesame Oil (Croda) Shark liveroil Super Refined Shark Liver Oil (Croda) Shea nut oil Soybean oil SuperRefined Soybean Oil (Croda) Stillingia oil Sunflower oil Tall oil Teaseed oil Tobacco seed oil Tung oil (China wood oil) Ucuhuba Vernonia oilWheat germ oil Super Refined Wheat Germ Oil (Croda) Hydrogenated castoroil Castorwax Hydrogenated coconut oil Pureco 100 (Abitec) Hydrogenatedcottonseed oil Dritex C (Abitec) Hydrogenated palm oil Dritex PST(Abitec); Softisan 154 (Hüls) Hydrogenated soybean oil Sterotex HM NF(Abitec); Dritex S (Abitec) Hydrogenated vegetable oil Sterotex NF(Abitec); Hydrokote M (Abitec) Hydrogenated cottonseed and castorSterotex K (Abitec) oil Partially hydrogenated soybean oil Hydrokote APS(Abitec) Partially hydrogenated soy and Apex B (Abitec) cottonseed oilGlyceryl mono-, di-, tri-behenate Compritol 888 Glycerol tributyrate(Sigma) Glyceryl tricaproate (Sigma) Glyceryl tricaprylate (Sigma)Glyceryl tricaprate Captex 1000 (Abitec) Glyceryl triundecanoate Captex8227 (Abitec) Glyceryl trilaurate (Sigma) Glyceryl trimyristate Dynasan114 (Hüls) Glyceryi tripalmitate Dynasan 116 (Hüls) Glyceryl tristearateDynasan 118 (Hüls) Glyceryl triarchidate (Sigma) Glyceryltrimyristoleate (Sigma) Glyceryl tripalmitoleate (Sigma) Glyceryltrioleate (Sigma) Glyceryl trilinoleate (Sigma) Glyceryl trilinolenate(Sigma) Glyceryl tricaprylate/caprate Captex 300 (Abitec); Captex 355(Abitec); Miglyol 810 (Hüls); Miglyol 312 (Hüls) Glyceryltricaprylate/caprate/laurate Captex 350 (Abitec) Glyceryltricaprylate/caprate/linoleate Captex 810 (Abitec); Miglyol 818 (Hüls)Glyceryl tricaprylate/caprate/stearate Softisan 378 (Hüls); (Larodan)Glyceryl tricaprylate/laurate/stearate (Larodan) Glyceryl1,2-caprylate-3-linoleate (Larodan) Glyceryl 1,2-caprate-3-stearate(Larodan) Glyceryl 1,2-laurate-3-myristate (Larodan) Glyceryl1,2-myristate-3-laurate (Larodan) Glyceryl 1,3-palmitate-2-butyrate(Larodan) Glyceryl 1,3-stearate-2-caprate (Larodan) Glyceryl1,2-linoleate-3-caprylate (Larodan)

In certain embodiments, the triglycerides utilized in the pharmaceuticalcompositions described herein include fractionated triglycerides,modified triglycerides, synthetic triglycerides, and mixtures oftriglycerides are also within the scope of the invention. In specificembodiments, triglycerides include, by way of non-limiting example,vegetable oils, fish oils, animal fats, hydrogenated vegetable oils,partially hydrogenated vegetable oils, medium and long-chaintriglycerides, and structured triglycerides. It should be appreciatedthat several commercial surfactant compositions contain small tomoderate amounts of triglycerides, typically as a result of incompletereaction of a triglyceride starting material in, for example, atransesterification reaction. Such commercial surfactant compositions,while nominally referred to as “surfactants”, may be suitable to provideall or part of the triglyceride component for the compositions of thepresent invention. Examples of commercial surfactant compositionscontaining triglycerides include some members of the surfactant familiesGelucires (Gattefosse), Maisines (Gattefosse), and Imwitors (Hüls).Specific examples of these compositions are: Gelucire 44/14 (saturatedpolyglycolized glycerides); Gelucire 50/13 (saturated polyglycolizedglycerides); Gelucire 53/10 (saturated polyglycolized glycerides):Gelucire 33/01 (semi-synthetic triglycerides of C₈-C₁₈ saturated fattyacids), Gelucire 39/01 (semi-synthetic glycerides), other Gelucires,such as 37/06, 43/01, 35/10, 37/02, 46/07, 48/09, 50/02, 62/05, or thelike; Maisine 35-I (linoleic glycerides); and Imwitor 742(capiylic/capric glycerides).

Additional Agents

The pharmaceutical compositions described herein optionally include oneor more additional agents or additives. In certain instances, suitableadditives include those that facilitate formulating a pharmaceuticalcomposition described herein as an oral dosage form and include, e.g.,coatings and capsule components. Further additives include, by way ofnon-limiting example, solubilizers, enzyme inhibitors, anti-foamingagents, antioxidants, binders, buffering agents, chelating agents,diluents, disintegrants, flavoring agents, preservatives, sweeteners,thickeners, or the like.

In some embodiments, pharmaceutical compositions provided hereinoptionally include one or more solubilizers, i.e., additives to increasethe solubility of the pharmaceutical active ingredient or othercomposition components in the solid carrier. Suitable solubilizers foruse in the compositions of the present invention include: alcohols,polyols, ethers of polyethylene glycols, amides, esters or the like.Alcohols and polyols include, by way of non-limiting example, ethanol,isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol,butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol,mannitol, transcutol, dimethyl isosorbide, polyethylene glycol,polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcelluloseand other cellulose derivatives, cyclodextrins and cyclodextrinderivatives. Ethers of polyethylene glycols include those having anaverage molecular weight of about 200 to about 6000, such as, by way ofnon-limiting example, tetrahydrofurfuryl alcohol PEG ether (glycofurol,available commercially from BASF under the trade name Tetraglycol) andmethoxy PEG (Union Carbide). Amides include, by way of non-limitingexample, 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone,N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam,dimethylacetamide, and polyinylpyrrolidone. Esters include, by way ofnon-limiting example, ethyl propionate, tributylcitrate, acetyltriethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate,ethyl caprylate, ethyl butyrate, triacetin, propylene glycolmonoacetate, propylene glycol diacetate, ε-caprolactone and isomersthereof, S-valerolactone and isomers thereof, β-butyrolactone andisomers thereof. Other solubilizers include, by way of non-limitingexample, dimethyl acetamide, dimethyl isosorbide (Arlasolve DMI (ICI)),N-methylpyrrolidones (Pharmasolve (ISP)), monooctanoin, diethyleneglycol monoethyl ether (available from Gattefosse under the trade nameTranscutol), and water. Mixtures of solubilizers are also within thescope of the present disclosure. Except as indicated, these compoundsare readily available from standard commercial sources. In specificembodiments, solubilizers include, by way of non-limiting example,triacetin, triethylcitrate, ethyl oleate, ethyl caprylate,dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone,polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcyclodextrins, ethanol, polyethylene glycol 200-600, glycofurol,transcutol, propylene glycol, and dimethyl isosorbide. In certainspecific embodiments, solubilizers include sorbitol, glycerol,triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol. Theamount of solubilizer included in the pharmaceutical compositionsdescribed herein is any suitable amount.

Anti-adherents (anti-sticking agents, glidants, flow promoters,lubricants) include, by way of non-limiting example, talc, magnesiumstearate, fumed silica (Carbosil, Aerosil), micronized silica (Syloid NoFP 244, Grace U.S.A.), polyethylene glycols, surfactants, waxes, stearicacid, stearic acid salts, stearic acid derivatives, starch, hydrogenatedvegetable oils, sodium benzoate, sodium acetate, leucine, PEG-4000 andmagnesium lauryl sulfate. Antioxidants include, by way of non-limitingexample, BHT, BHA, gallic acid, propyl gallate, ascorbic acid, ascorbylpalmitate, 4-hydroxymethyl-2,6-di-tert-butyl phenol, and tocopherol.Binders (adhesives), i.e., agents that impart cohesive properties topowdered materials through particle-particle bonding, include, by way ofnon-limiting example, matrix binders (dry starch, dry sugars), filmbinders (PVP, starch paste, celluloses, bentonite, sucrose), andchemical binders (polymeric cellulose derivatives, such as carboxymethyl cellulose, HPC and HPNC, sugar syrups; corn syrup; water solublepolysaccharides such as acacia, tragacanth, guar and alginates; gelatin,gelatin hydrolysate; agar; sucrose; dextrose, and non-cellulosicbinders, such as PVP, PEG, vinyl pyrrolidone copolymers, pregelatinizedstarch, sorbitol, and glucose) Buffering agents, include an acid and abase, wherein the acid is a pharmaceutically acceptable acid, such ashydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid,nitric acid, boric acid, phosphoric acid, acetic acid, acrylic acid,adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbicacid, benzoic acid, boric acid, butyric acid, carbonic acid, citricacid, fatty acids, formic acid, fumaric acid, gluconic acid,hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid,methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid,propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid,succinic acid, tannic acid, tartaric acid, thioglycolic acid,toluenesulfonic acid and uric acid, and the base is a pharmaceuticallyacceptable base, such as an amino acid, an amino acid ester, ammoniumhydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogencarbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide,magnesium aluminum silicate, synthetic aluminum silicate, synthetichydrotalcite, magnesium aluminum hydroxide, diisopropylethylamine,ethanolamine, ethylenediamine, triethanolamine, triethylamine,triisopropanolamine, or a salt of a pharmaceutically acceptable cationand acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonicacid, an amino acid, ascorbic acid, benzoic acid, boric acid, butyricacid, carbonic acid, citric acid, a fatty acid, formic acid, fumaricacid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lacticacid, maleic acid, methanesulfonic acid, oxalic acid,para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid,salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid,thioglycolic acid, toluenesulfonic acid, and uric acid. Chelating agentsinclude, by way of non-limiting example, EDTA and EDTA salts Colorantsor opaquants include, by way of non-limiting example, titanium dioxide,food dyes, lakes, natural vegetable colorants, iron oxides, silicates,sulfates, magnesium hydroxide and aluminum hydroxide. Diluents orfillers include, by way of non-limiting example, lactose, mannitol,talc, magnesium stearate, sodium chloride, potassium chloride, citricacid, spray-dried lactose, hydrolyzed starches, directly compressiblestarch, microcrystalline cellulose, cellulosics, sorbitol, sucrose,sucrose-based materials, calcium sulfate, dibasic calcium phosphate anddextrose. Disintegrants and super disintegrants include, by way ofnon-limiting example, croscarmellose sodium, starch, starch derivatives,clays, gums, cellulose, cellulose derivatives, alginates, crosslinkedpolyvinylpyrrolidone, sodium starch glycolate and microcrystallinecellulose. Flavorants or desensitizers include, by way of non-limitingexample, spray-dried flavors, essential oils and ethyl vanillin.Plasticizers include, by way of non-limiting example, polyethyleneglycol, citrate esters (e.g., triethyl citrate, acetyl triethyl citrate,acetyltributyl citrate), acetylated monoglycerides, glycerin, triacetin,propylene glycol, phthalate esters (e.g., diethyl phthalate, dibutylphthalate), castor oil, sorbitol and dibutyl seccate. Preservativesinclude, by way of non-limiting example, ascorbic acid, boric acid,sorbic acid, benzoic acid, and salts thereof, parabens, phenols, benzylalcohol, and quaternary ammonium compounds. Solvents include, by way ofnon-limiting example, alcohols, ketones, esters, chlorinatedhydrocarbons and water. Sweeteners include, by way of non-limitingexample, natural sweeteners such as maltose, sucrose, glucose, sorbitol,glycerin and dextrins, and artificial sweeteners, such as aspartame,saccharine and saccharine salts. Thickeners (viscosity modifiers,thickening agents) include, by way of non-limiting example, sugars,polyvinylpyrrolidone, cellulosics, polymers, high molecular weightpolyethylene glycols (e.g., PEG 8000), and alginates. Additives alsoinclude, by way of non-limiting example, proteins (e.g., collagen,gelatin, Zein, gluten, mussel protein, lipoprotein); carbohydrates(e.g., alginates, carrageenan, cellulose derivatives, pectin, starch,chitosan): gums (e.g., xanthan gum, gum arabic); spermaceti; natural orsynthetic waxes; carnuaba wax, fatty acids (e.g, stearic acid,hydroxystearic acid), fatty alcohols; sugars; shellacs, such as thosebased on sugars (e.g., lactose, sucrose, dextrose) or starches:polysaccharide-based shellacs (e.g., maltodextrin and maltodextrinderivatives, dextrates, cyclodextrin and cyclodextrin derivatives);cellulosic-based shellacs (e.g., microcrystalline cellulose, sodiumcarboxymethyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose,hydroxypropyl cellulose, cellulose acetate, cellulose nitrate, celluloseacetate butyrate, cellulose acetate trimellitate, carboxymethylethylcellulose, hydroxypropylmethyl cellulose phthalate); inorganics, such asdicalcium phosphate, hydroxyapitite, tricalcium phosphate, talc andtitania; polyols, such as mannitol, xylitol and sorbitol, polyethyleneglycol esters; and polymers, such as alginates, poly(lactidecoglycolide), gelatin, crosslinked gelatin, and agar-agar.

It should be appreciated that there is considerable overlap between theabove-listed additives in common usage, since a given additive is oftenclassified differently by different practitioners in the field, or iscommonly used for any of several different functions. Thus, theabove-listed additives should be taken as merely exemplary, and notlimiting, of the types of additives that can be included in compositionsof the present invention. The amounts of such additives can be readilydetermined by one skilled in the art, according to the particularproperties desired.

The compositions and unit dosage forms can be prepared by any suitablemethod known to the skilled artisan or developed in view of theteachings herein.

In one specific aspect, the carrier(s) and API are brought to ormaintained at a temperature at which they are flowable (e.g., above 10°C., 20° C., 25° C., 30° C., 35° C., or 40° C.). In one aspect, themixture of carrier and API is a clear solution at a specifiedtemperature (e.g., above 10° C., 20° C., 25° C., 30° C., 35° C., or 40°C.). In one aspect, the mixture of carrier and API is a cloudy or hazysolution at a specified temperature (e.g., below 10° C., 20° C., 25° C.,30° C., 35° C., or 4° C.).

In one example, the composition is prepared by weighing all of thecomponents, except the API into a clean stainless steel container andmixed together at ambient temperature or at elevated temperatures e.g.,at about 25° C. to about 30° C., at about 30° C. to about 35° C., atabout 35° C. to about 40° C., at about 40° C. to about 45° C., at about45° C. to about 45° C., or 50° C. to about 70° C., using a stirrer. TheAPI is added and stirred into the mixture of other components until theAPI dissolves. A predetermined quantity of this “liquid fill material”is disposed into a capsule (for example, hard gelatin capsule) to getthe required API dose per dosage unit. The capsules are allowed to coolat room temperature, banded (if required) and packaged in a HDPE bottleand tightly closed with an appropriate lid. It is noted that variouscapsule sizes (e.g., hard gel or soft gel) are available to the skilledartisan and allow for variations in the amount of loading of API in mgper unit dosage form. Typically, soft gel capsules for oraladministration have fill volumes of less than 1.5 mL, 1.3 mL or 1.25 mLwith numerous incremental fill volumes in these ranges. Similarly, hardgel capsules typically have fill volumes of less than 1.25 mL, 1.10 mLor 1 mL. Due to the nature of some hard gel capsules, the total fillvolume may not be useable. There is a practical limit on the temperatureat which capsules can be filled—for example temperature above 40° C.typically melt, deform, or otherwise damage soft gel capsules typicallyemployed in the industry. Hard gel capsules are typically less sensitiveto temperature and can be filled at higher temperatures e.g., above 40°C.

In certain embodiments, any pharmaceutical composition described herein,e.g., a can be prepared by (i) combining and heating all ingredientsuntil a molten mixture is obtained (e.g., 50-70° C.); and (ii)encapsulating an amount of molten mixture comprising a select dose(e.g., a therapeutically effective amount or a partial dose of atherapeutically effective amount) API to obtain an oral dosage form. Incertain instances, the molten mixture is spray-congealed to obtainbeads. In some instances, the molten mixture is sprayed onto inert cores(e.g., sugar spheres) to obtain coated cores. In certain embodiments,such beads, cores, or similar forms are encapsulated or otherwiseformulated to provide an oral dosage form. In some instances, the moltenmixture is admixed, uniformly dispersed, or granulated over a carrierand compressed into a tablet dosage form. In certain embodiments, priorto compression, the molten mixture/carrier composition is further mixedwith one or more pharmaceutical aid including, by way of non-limitingexample, glidants, lubricants, binders, or the like. In someembodiments, the carrier is a therapeutically inert carrier such as, byway of non-limiting example, microcrystalline cellulose, starch,lactose, or the like.

In various embodiments, pharmaceutical compositions described herein areformulated as oral dosage forms. Oral dosage forms are prepared by anysuitable process including one or more steps of, by way of non-limitingexample, agglomeration, air suspension chilling, air suspension drying,balling, coacervation, comminution, compression, pelletization,cryopelletization, encapsulation, extrusion, granulation,homogenization, inclusion complexation, lyophilization,nanoencapsulation, melting, mixing, molding, pan coating, solventdehydration, sonication, spheronization, spray chilling, spraycongealing, spray drying, or the like.

In some embodiments, a pharmaceutical composition described herein isformulated with a substrate to form an oral dosage form. In variousembodiments, substrates useful for formulating pharmaceuticalcompositions described herein as oral dosage forms include or comprise,by way of non-limiting example, a powder or a multiparticulate (e.g.,one or more granule, one or more pellet, one or more bead, one or morespherule, one or more beadlet, one or more microcapsule, one or moremillisphere, one or more mini capsule, one or more microcapsule, one ormore nanocapsule, one or more nanosphere, one or more micrsphere, one ormore minitablet, one or more tablet, one or more capsule, or one or morecombinations thereof). In certain instances, a powder constitutes afinely divided (milled, micronized, nanosized, precipitated) form of anactive ingredient or additive molecular aggregates or a compoundaggregate of multiple components or a physical mixture of aggregates ofan active ingredient and/or additives.

Exemplary Formulation Embodiments

Provided in this section are formulations for use in the methodsdescribed herein. It is noted that any testosterone ester can used inplace of the specified API (e.g., testosterone undecanoate or acombination of testosterone undecanoate and testosterone tridecanoate).

TABLE 1A Drug + Carriers Compositions (w/w %) Ratio of API: Carrier in aTestosterone pharmaceutical Composition tridecanoate* Carriercomposition A  5-15 85-95 1:5.7-1:9.0 B 15-20 80-85 1:4.0-1:5.7 C 20-3070-80 1:2.3-1:4.0 D 30-40 60-70 1:1.5-1:2.3 E 40-50 50-60 1:1.0-1:1.5*As an active ingredient, it can be untreated, sieved (PS < 450 micron),milled (PS < 150 micron), micronized (1 micron < PS < 25 micron), ornanosized (PS < 1 micron).

TABLE 2A Carrier Components Carrier No. Component I II III IV V VI VIIVIII IX X XI XII XIII Solubilizer Propylene Y — — — — — — — — — — — —glycol mono or di-laurate Propylene — Y — — — — — — — — — — — glycolmono or di-caprylate Corn — — Y — — — — — — — — — — glycerides (e.g.Glyceryl mono or di-linoleate) Vegetable — — — Y — — — — — — — — —glycerides (e.g. Glyceryl mono or di-oleate) Glyceryl mono — — — — Y — —— — — — — — or di-stearate Glyceryl — — — — — Y — — — — — — — palmito-stearate (9Z)-Octadec- — — — — — — Y — — — — — — 9-enoic acidOctadecanoic — — — — — — — Y — — — — — acid (9Z,12Z)-9,12- — — — — — — —— Y — — — — Octa- decadienoic acid Peppermint oil — — — — — — — — — Y —— — Omega-3 — — — — — — — — — — Y — — EPA/DHA Vitamin E — — — — — — — —— — — Y — Combinations — — — — — — — — — — — — Y * HydrophilicCremophor, Y Y Y Y Y Y Y Y Y Y Y Y Y Add. Tween, SLS, Poloxamer,Polymer, and/or combinations Other Anti-oxidant, q.s. q.s. q.s. q.s.q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. Add. solidifier, flowagent, solvent, and/or combinations * Combinations of solubilizers canbe a combination of 2 or more solubilizers that are listed in this tableas well as include propylene glycol, polyethylene glycol, glycerol,sorbitol, DMA, and so on. Add. = additive. Y = Yes. Carrier I.Compositions composed of solubilizer (Propylene glycol mono ordi-laurate), hydrophilic additives, and other additives for CompositionA to E % Carrier Compositions (w/w %) Release in Hydrophilic 8% Tritonadditives¹ (e.g. Aqueous Cremophor² RH Media 40, Tween³ 80, ≥50% inPropylene SLS, Poloxamer⁴ 2 hrs glycol 407, Polymer⁵, Other additives⁷Total % and Comp. mono or and/or Anti- Solidify Combin- in ≥75% I No.di-laurate combinations⁶) oxidant⁸ agent⁹ ations¹⁰ Carrier in 4 hrs a 90-100 — 0-1  0-10  0-10 100 Yes b 45-99  1-40 0-1  0-15  0-15 100 Yes 1-25 0-1 15-20 15-20 100 No c 85-99   1-4.5 0-1  0-10  0-10 100 Yes d80-95  5-10 0-1  0-10  0-10 100 Yes e 70-90 10-20 0-1  0-10  0-10 100Yes f 60-80 20-30 0-1  0-10  0-10 100 Yes 10-20 0-1 10-20 10-20 100 No g50-80 30-40 0-1  0-10  0-10 100 Yes 20-30 0-1  0-10  0-10 100 Yes 10-200-1 10-20 10-20 100 No ¹Hydrophilic additives can be, but are notlimited to ones listed in this table, e.g., hydrophilic surfactantshaving an HLB value of greater than 10, which are PEG-8 caprylic/capricglycerides (Labrasol), lauroyl macrogol-32 glyceride (Gelucire 44/14),stearoyl macrogol glyceride (Gelucire 50/13), sodium dioctylsulfosuccinate, polyethylene glycol fatty acids mono- and di-estermixtures, polyethylene glycol 1000 tocopherol succinate, phytosterols,phytosterol fatty acid esters, lanosterol PEG-24 cholesterol ether,PEG-30 soya sterol, PEG-25 phyto sterol, PEG-30 cholestanol, and so on.²Cremophor includes, but is not limited to, Cremophor RH 40, butCremophor EL, RH 40, and RH 60. ³Tween includes, but is not limited to,Tween 80, but Tween 20, 60, and 80. ⁴Poloxamer includes, but is notlimited to Poloxamer 407, but Poloxamer 124, 188, 234, 335, and 407.⁵Polymer includes, but is not limited to, Polyethylene glycol,Hydroxypropyl cellulose, Hydroxypropylmethyl cellulose,Hydroxypropylmethyl cellulose acetate succinate, Polyvinylpyrrolidone,Polyvinyl acetate, Polylactic-co-glycolic acid, Polyvinyl caprolactame,Carbomer, and a combination thereof ⁶Combinations of hydrophilicadditives can be 2 or more hydrophilic additives. ⁷Other additives canbe, but are not limited to ones listed in this table, e.g., adsorbingagents, anti-adherents, anticoagulants, antifoaming agents, anti-cakingagents, anti-static agents, binders, bile acids, bufferants, bulkingagents, chelating agents, coagulants, colorants, opaquants, coolants,cryoprotectants, diluents, dehumidifying agents, desiccants,desensitizers, disintegrants, dispersing agents, enzyme inhibitors,fillers, hydrating agent, super disintegrants, gums, mucilages, hydrogenbonding agents, enzymes, flavorants, humectants, humidifying agents,ion-exchange resins, lubricants, plasticizers, pH modifying agents,preservatives, organic solvents, spreading agent, stabilizers,suspending agent, thickeners, viscosity increasing agents, waxes, and soon. 8Anti-oxidant can be, but is not limited to, ascorbyl palmitate,ascorbic acid, butylated hydroxyanisole (BHA), butylated hydroxytoluene(BHT), propyl gallate, cysteine, sodium metabisulfite (SMB), thiolderivatives, alpha-tocopherol, and so on. ⁹Solidifying (solidify) agentcan be, but is not limited, to PEG 3350, PEG 4000, PEG 6000, PEG 8000,Poloxamer 188, Poloxamer 407, cetyl esters, wax, beeswax, glycerylmonostearate, glyceryl distearate, glyceryl palmitostearate, stearicacid, and so on. ¹⁰Combinations of other additives can be 2 or moreother additives. Descriptions for from ¹ to ¹⁰ are applied to tables ofall carrier compositions (from Carrier I to Carrier XIII tables) shownbelow. Carrier II. Compositions composed of solubilizer (Propyleneglycol mono or di-caprylate), hydrophilic additives, and other additivesfor Composition A to E % Carrier Compositions (w/w %) Release inHydrophilic 8% Triton additives¹ (e.g. Aqueous Cremophor² RH Media 40,Tween³ 80, ≥50% in Propylene SLS, Poloxamer⁴ 2 hrs glycol 407, Polymer⁵,Other additives⁷ Total % and Comp. mono or and/or Anti- Solidify Combin-in ≥75% II No. di-caprylate combinations⁶) oxidant⁸ agent⁹ ations¹⁰Carrier in 4 hrs a  90-100 — 0-1  0-10  0-10 100 Yes b 45-99  1-40 0-1 0-15  0-15 100 Yes  1-25 0-1 15-20 15-20 100 No c 85-99   1-4.5 0-1 0-10  0-10 100 Yes d 80-95  5-10 0-1  0-10  0-10 100 Yes e 70-90 10-200-1  0-10  0-10 100 Yes f 60-80 20-30 0-1  0-10  0-10 100 Yes 10-20 0-110-20 10-20 100 No g 50-80 30-40 0-1  0-10  0-10 100 Yes 20-30 0-1  0-10 0-10 100 Yes 10-20 0-1 10-20 10-20 100 No Carrier III. Compositionscomposed of solubilizer (Com glycerides: e.g. Glyceryl mono ordi-linoleate), hydrophilic additives, and other additives forComposition A to E % Carrier Compositions (w/w %) Release in Hydrophilic8% Triton Corn additives¹ (e.g. Aqueous glycerides Cremophor² RH Media(e.g. 40, Tween³ 80, ≥50% in Glyceryl SLS, Poloxamer⁴ 2 hrs mono or 407,Polymer⁵, Other additives⁷ and Comp. di- and/or Anti- Solidify Combin-Total % ≥75% III No. linoleate) combinations⁶) oxidant⁸ agent⁹ ations¹⁰in Carrier in 4 hrs a  90-100 — 0-1  0-10  0-10 100 Yes b 45-99  1-400-1  0-15  0-15 100 Yes  1-25 0-1 15-20 15-20 100 No c 85-99   1-4.5 0-1 0-10  0-10 100 Yes d 80-95  5-10 0-1  0-10  0-10 100 Yes e 70-90 10-200-1  0-10  0-10 100 Yes f 60-80 20-30 0-1  0-10  0-10 100 Yes 10-20 0-110-20 10-20 100 No g 50-80 30-40 0-1  0-10  0-10 100 Yes 20-30 0-1  0-10 0-10 100 Yes 10-20 0-1 10-20 10-20 100 No Carrier IV. Compositionscomposed of solubilizer (Vegetable glycerides: e.g. Glyceryl mono or di-oleate), hydrophilic additives, and other additives for Composition A toE % Carrier Compositions (w/w %) Release in Hydrophilic 8% Tritonadditives¹ (e.g. Aqueous Vegetable Cremophor² RH Media glycerides 40,Tween³ 80, ≥50% in (e.g. SLS, Poloxamer⁴ 2 hrs Glyceryl 407, Polymer⁵,Other additives⁷ and Comp. mono or and/or Anti- Solidify Combin- Total %≥75% IV No. di-oleate) combinations⁶) oxidant⁸ agent⁹ ations¹⁰ inCarrier in 4 hrs a  90-100 — 0-1  0-10  0-10 100 Yes b 45-99  1-40 0-1 0-15  0-15 100 Yes  1-25 0-1 15-20 15-20 100 No c 85-99   1-4.5 0-1 0-10  0-10 100 Yes d 80-95  5-10 0-1  0-10  0-10 100 Yes e 70-90 10-200-1  0-10  0-10 100 Yes f 60-80 20-30 0-1  0-10  0-10 100 Yes 10-20 0-110-20 10-20 100 No g 50-80 30-40 0-1  0-10  0-10 100 Yes 20-30 0-1  0-10 0-10 100 Yes 10-20 0-1 10-20 10-20 100 No Carrier V. Compositionscomposed of solubilizer (Glyceryl mono or di-stearate), hydrophilicadditives, and other additives for Composition A to E % CarrierCompositions (w/w %) Release in Hydrophilic 8% Triton additives¹ (e.g.Aqueous Cremophor² RH Media 40, Tween³ 80, ≥50% in Glyceryl SLS,Poloxamer⁴ 2 hrs mono or 407, Polymer⁵, Other additives⁷ and Comp. di-and/or Anti- Solidify Combin- Total % ≥75% V stearate combinations⁶)oxidant⁸ agent⁹ ations¹⁰ in Carrier in 4 hrs a  90-100 — 0-1  0-10  0-10100 No b 45-99  1-40 0-1  0-15  0-15 100 No  1-25 0-1 15-20 15-20 100 Noc 85-99   1-4.5 0-1  0-10  0-10 100 No d 80-95  5-10 0-1  0-10  0-10 100No e 70-90 10-20 0-1  0-10  0-10 100 No f 60-80 20-30 0-1  0-10  0-10100 No 10-20 0-1 10-20 10-20 100 No g 50-80 30-40 0-1  0-10  0-10 100 No20-30 0-1  0-10  0-10 100 No 10-20 0-1 10-20 10-20 100 No Carrier VI.Compositions composed of solubilizer (Glyceryl palmito-stearate),hydrophilic additives, and other additives for Composition A to E %Carrier Compositions (w/w %) Release in Hydrophilic 8% Triton additives¹(e.g. Aqueous Cremophor² RH Media 40, Tween³ 80, ≥50% in SLS, Poloxamer⁴2 hrs Glyceryl 407, Polymer⁵, Other additives⁷ and Comp. palmito- and/orAnti- Solidify Combin- Total % ≥75% VI No. stearate combinations⁶)oxidant⁸ agent⁹ ations¹⁰ in Carrier in 4 hrs a  90-100 — 0-1  0-10  0-10100 No b 45-99  1-40 0-1  0-15  0-15 100 No  1-25 0-1 15-20 15-20 100 Noc 85-99   1-4.5 0-1  0-10  0-10 100 No d 80-95  5-10 0-1  0-10  0-10 100No e 70-90 10-20 0-1  0-10  0-10 100 No f 60-80 20-30 0-1  0-10  0-10100 No 10-20 0-1 10-20 10-20 100 No g 50-80 30-40 0-1  0-10  0-10 100 No20-30 0-1  0-10  0-10 100 No 10-20 0-1 10-20 10-20 100 No Carrier VII.Compositions composed of solubilizer ((9Z)-Octadec-9-enoic acid),hydrophilic additives, and other additives for Composition A to E %Carrier Compositions (w/w %) Release in Hydrophilic 8% Triton additives¹(e.g. Aqueous Cremophor² RH Media 40, Tween³ 80, ≥50% in (9Z)- SLS,Poloxamer⁴ 2 hrs Octadec- 407, Polymer⁵, Other additives⁷ and Comp9-enoic and/or Anti- Solidify Combin- Total % ≥75% VII No. acidcombinations⁶) oxidant⁸ agent⁹ ations¹⁰ in Carrier in 4 hrs a  90-100 —0-1  0-10  0-10 100 Yes b 45-99  1-40 0-1  0-15  0-15 100 Yes  1-25 0-115-20 15-20 100 No c 85-99   1-4.5 0-1  0-10  0-10 100 Yes d 80-95  5-100-1  0-10  0-10 100 Yes e 70-90 10-20 0-1  0-10  0-10 100 Yes f 60-8020-30 0-1  0-10  0-10 100 Yes 10-20 0-1 10-20 10-20 100 No g 50-80 30-400-1  0-10  0-10 100 Yes 20-30 0-1  0-10  0-10 100 Yes 10-20 0-1 10-2010-20 100 No Carrier VIII. Compositions composed of solubilizer(octadecanoic acid), hydrophilic additives, and other additives forComposition A to E % Carrier Compositions (w/w %) Release in Hydrophilic8% Triton additives¹ (e.g. Aqueous Cremophor² RH Media 40, Tween³ 80,≥50% in SLS, Poloxamer⁴ 2 hrs Octa- 407, Polymer⁵, Other additives⁷ andComp. decanoic and/or Anti- Solidify Combin- Total % ≥75% VIII No. acidcombinations⁶) oxidant⁸ agent⁹ ations¹⁰ in Carrier in 4 hrs a  90-100 —0-1  0-10  0-10 100 No b 45-99  1-40 0-1  0-15  0-15 100 No  1-25 0-115-20 15-20 100 No c 85-99   1-4.5 0-1  0-10  0-10 100 No d 80-95  5-100-1  0-10  0-10 100 No e 70-90 10-20 0-1  0-10  0-10 100 No f 60-8020-30 0-1  0-10  0-10 100 No 10-20 0-1 10-20 10-20 100 No g 50-80 30-400-1  0-10  0-10 100 No 20-30 0-1  0-10  0-10 100 No 10-20 0-1 10-2010-20 100 No Carrier IX. Compositions composed of solubilizer((9Z,12Z)-9,12-Octadecadienoic acid), hydrophilic additives, and otheradditives for Composition A to E % Carrier Compositions (w/w %) Releasein Hydrophilic 8% Triton additives¹ (e.g. Aqueous Cremophor² RH Media(9Z,12Z)- 40, Tween³ 80, ≥50% in 9,12- SLS, Poloxamer⁴ 2 hrs Octadec-407, Polymer⁵, Other additives⁷ and Comp. adienoic and/or Anti- SolidifyCombin- Total % ≥75% IX No. acid combinations⁶) oxidant⁸ agent⁹ ations¹⁰in Carrier in 4 hrs a  90-100 — 0-1  0-10  0-10 100 Yes b 45-99  1-400-1  0-15  0-15 100 Yes  1-25 0-1 15-20 15-20 100 No c 85-99   1-4.5 0-1 0-10  0-10 100 Yes d 80-95  5-10 0-1  0-10  0-10 100 Yes e 70-90 10-200-1  0-10  0-10 100 Yes f 60-80 20-30 0-1  0-10  0-10 100 Yes 10-20 0-110-20 10-20 100 No g 50-80 30-40 0-1  0-10  0-10 100 Yes 20-30 0-1  0-10 0-10 100 Yes 10-20 0-1 10-20 10-20 100 No Carrier X. Compositionscomposed of solubilizer (Peppermint oil), hydrophilic additives, andother additives for Composition A to E % Carrier Compositions (w/w %)Release in Hydrophilic 8% Triton additives¹ (e.g. Aqueous Cremophor² RHMedia 40, Tween³ 80, ≥50% in SLS, Poloxamer⁴ 2 hrs 407, Polymer⁵, Otheradditives⁷ and Comp. Peppermint and/or Anti- Solidify Combin- Total %≥75% X oil combinations⁶) oxidant⁸ agent⁹ ations¹⁰ in Carrier in 4 hrs a 90-100 — 0-1  0-10  0-10 100 Yes b 45-99  1-40 0-1  0-15  0-15 100 Yes 1-25 0-1 15-20 15-20 100 Yes c 85-99   1-4.5 0-1  0-10  0-10 100 Yes d80-95  5-10 0-1  0-10  0-10 100 Yes e 70-90 10-20 0-1  0-10  0-10 100Yes f 60-80 20-30 0-1  0-10  0-10 100 Yes 10-20 0-1 10-20 10-20 100 Yesg 50-80 30-40 0-1  0-10  0-10 100 Yes 20-30 0-1  0-10  0-10 100 Yes10-20 0-1 10-20 10-20 100 Yes Carrier XI. Compositions (Omega-3hydrophilic composed of solubilizer EPA/DHA), additives, % CarrierCompositions (w/w %) Release in Hydrophilic 8% Triton additives¹ (e.g.Aqueous Cremophor² RH Media 40, Tween³ 80, ≥50% in SLS, Poloxamer⁴ 2 hrs407, Polymer⁵, Other additives⁷ and Comp. Omega-3 and/or Anti- SolidifyCombin- Total % ≥75% XI No. EPA/DHA combinations⁶) oxidant⁸ agent⁹ations¹⁰ in Carrier in 4 hrs a  90-100 — 0-1  0-10  0-10 100 Yes b 45-99 1-40 0-1  0-15  0-15 100 Yes  1-25 0-1 15-20 15-20 100 No c 85-99  1-4.5 0-1  0-10  0-10 100 Yes d 80-95  5-10 0-1  0-10  0-10 100 Yes e70-90 10-20 0-1  0-10  0-10 100 Yes f 60-80 20-30 0-1  0-10  0-10 100Yes 10-20 0-1 10-20 10-20 100 No g 50-80 30-40 0-1  0-10  0-10 100 Yes20-30 0-1  0-10  0-10 100 Yes 10-20 0-1 10-20 10-20 100 No Carrier XII.Compositions composed of solubilizer (Vitamin E), hydrophilic additives,and other additives for Composition A to E % Release in Hydrophilic 8%Triton additives¹ (e.g. Aqueous Cremophor² RH Media 40, Tween³ 80, ≥50%in SLS, Poloxamer⁴ 2 hrs 407, Polymer⁵, Other additives⁷ and Comp.and/or Anti- Solidify Combin- Total % ≥75% XII No. Vitamin Ecombinations⁶) oxidant⁸ agent⁹ ations¹⁰ in Carrier in 4 hrs a  90-100 —0-1  0-10  0-10 100 Yes b 45-99  1-40 0-1  0-15  0-15 100 Yes  1-25 0-115-20 15-20 100 Yes c 85-99   1-4.5 0-1  0-10  0-10 100 Yes d 80-95 5-10 0-1  0-10  0-10 100 Yes e 70-90 10-20 0-1  0-10  0-10 100 Yes f60-80 20-30 0-1  0-10  0-10 100 Yes 10-20 0-1 10-20 10-20 100 Yes g50-80 30-40 0-1  0-10  0-10 100 Yes 20-30 0-1  0-10  0-10 100 Yes 10-200-1 10-20 10-20 100 Yes Carrier XIII. Compositions composed of acombination of solubilizers, hydrophilic additives, and other additivesfor Composition A to E % Carrier Compositions (w/w %) Release inCombination of Hydrophilic 8% Triton solubilizers^(†) additives¹ (e.g.Aqueous (e.g. oleic Cremophor² RH Media acid and GDS, oleic 40, Tween³80, ≥50% in acid and SLS, Poloxamer⁴ 2 hrs peppermint 407, Polymer⁵,Other additives⁷ and Comp. oil, maisine and/or Anti- Solidify Combin-Total % ≥75% XIII No. 35-1 and GMC, etc) combinations⁶) oxidant⁸ agent⁹ations¹⁰ in Carrier in 4 hrs a  90-100 — 0-1  0-10  0-10 100 Yes b 45-99 1-40 0-1  0-15  0-15 100 Yes  1-25 0-1 15-20 15-20 100 No c 85-99  1-4.5 0-1  0-10  0-10 100 Yes d 80-95  5-10 0-1  0-10  0-10 100 Yes e70-90 10-20 0-1  0-10  0-10 100 Yes f 60-80 20-30 0-1  0-10  0-10 100Yes 10-20 0-1 10-20 10-20 100 No g 50-80 30-40 0-1  0-10  0-10 100 Yes20-30 0-1  0-10  0-10 100 Yes 10-20 0-1 10-20 10-20 100 No

Shown below are various compositions suitable for oral administration asdescribed herein. In these Examples the amount of excipient adds up to100% (does not include the API) and the API weight percent is the finalweight percent in the pharmaceutical composition.

Composition No. Component (w/w %) 1 2 3 4 5 6 7 API 22 23 24 26 28 30 32Excipient 1 35-80 35-80 35-80 35-80 35-80 35-80 35-80 (e.g., liquidcarrier) Excipient 2  1-40  1-40  1-40  1-40  1-40  1-40  1-40 (e.g.,additive)               Excipient 3  0-20  0-20  0-20  0-20  0-20  0-20 0-20 (e.g., hydrophilic additive) Excipient 4 0.01-3   0.01-3  0.01-3   0.01-3   0.01-3   0.01-3   0.01-3   (e.g., anti-oxidant)Additional Qs qs qs qs qs Qs qs Excipients (e.g., other pharmaceuticallyacceptable excipients)

The API in these compositions in specific compositions is testosteronetridecanoate, testosterone undecanoate, or a combination thereof.Alternatively, the skilled artisan understands that any othertestosterone ester or steroid, or steroid ester can be used in thesecompositions accordingly. Excipient 1 in specific compositions is(9Z)-octadec-9-enoic acid. Excipient 2 in specific compositions is acombination of mono-, di-, or tri-propane-1,2,3-triol esters ofoctadecanoic acid and hexadecanoic acid; H—(O—CH₂—CH₂)_(n)—OH where n isan integer from 3 to 900; octadecanoic acid;(1R,2S,5R)-2-isopropyl-5-methylcyclohexanol or a combination of one ormore of (1R,2S,5R)-2-isopropyl-5-methylcyclohexanol,(2S,5R)-2-Isopropyl-5-methylcyclohexanone, Acetic acid[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]ester,1,3,3-Trimethyl-2-oxabicyclo[2,2,2]octane, and(R)-1-methyl-4-(1-methylethenyl)cyclohexene; or a combination thereof.Excipient 3 in specific compositions is a polyoxylated hydrogenatedvegetable oil. Excipient 4 in specific compositions is ascorbylpalmitate. These compositions can be filled into soft gel or hard gelcapsules depending on its flowability at the temperatures useful formaking these dosage forms.

Exemplary Compositions

Shown below are various compositions suitable for oral administration asdescribed herein. In these Examples the amount of excipient adds up to100% (does not include the API) and the API weight percent is the finalweight percent in the pharmaceutical composition.

Composition No. Component (w/w %) 10 11 12 13 14 15 16 17 18 API 23 2425 26 27 28 29 30 31 Excipient 1 40-70 30-70 40-70 40-70 40-70 40-7040-70 30-70 40-70 (e.g., C14-C20 fatty acid) Excipient 2 0.5-20   1-20 1-20 (e.g., glyceryl palmitostearate) Excipient 3 0.5-30   5-35 10-30Excipient 4 0.5-15   1-12  2-11 (e.g., polyethylene glycol (highmolecular weight)) Excipient 4 0.01-3   0.01-3   0.01-3   0.01-3  0.01-3   0.01-3   0.01-3   0.01-3   0.01-3   (e.g., anti-oxidant(ascorbyl palmitate) Additional qs qs qs Qs qs Qs qs qs qs Excipients

The API in these compositions in specific compositions is testosteronetridecanoate, testosterone undecanoate, or a combination thereof.Alternatively, the skilled artisan understands that any othertestosterone ester or steroid, or steroid ester can be used in thesecompositions accordingly. Excipient 1 in specific compositions is(9Z)-octadec-9-enoic acid. Excipient 2 in specific compositions is acombination of mono-, di-, or tri-propane-1,2,3-triol esters ofoctadecanoic acid and hexadecanoic acid, octadecanoic acid or acombination thereof. Excipient 3 in specific compositions is(R,2S,5R)-2-isopropyl-5-methylcyclohexanol or a combination of one ormore of (R,2S,5R)-2-isopropyl-5-methylcyclohexanol,(2S,5R)-2-Isopropyl-5-methylcyclohexanone, Acetic acid[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]ester,1,3,3-Trimethyl-2-oxabicyclo[2,2,2]octane, and(R)-1-methyl-4-(1-methylethenyl)cyclohexene. Excipient 4 in specificcompositions is H—(O—CH₂—CH₂)_(n)—OH where n is an integer from 3 to 900(e.g., PEG having an average molecular weight in the range of2000-12000). These compositions can be filled into soft gel or hard gelcapsules depending on its flowability at the temperatures useful formaking these dosage forms. These compositions may include a hydrophilicadditive.

Shown below are various compositions suitable for oral administration asdescribed herein. In these Examples the amount of excipient adds up to100% (does not include the API) and the API weight percent is the finalweight percent in the pharmaceutical composition.

Composition No. Component (w/w %) 19 20 21 22 23 24 25 26 27 API 23 2425 26 27 28 29 30 31 Excipient 1 40-90 40-90 40-90 40-90 40-90 40-9040-90 40-90 40-90 Excipient 2  1-20  1-20  1-20  1-20  1-20 Excipient 3 1-10  1-10  1-10  1-10 Excipient 4  0-25  0-25  0-25  0-25  0-25  0-25 0-25  0-25  0-25 Additional qs qs qs qs qs qs Qs qs qs Excipients

The API in these compositions in specific compositions is testosteronetridecanoate, testosterone undecanoate, or a combination thereof.Alternatively, the skilled artisan understands that any othertestosterone ester or steroid, or steroid ester can be used in thesecompositions accordingly. Excipient 1 in specific compositions is(9Z)-octadec-9-enoic acid. Excipient 2 in specific compositions is acombination of mono-, di-, or tri-propane-1,2,3-triol esters ofoctadecanoic acid and hexadecanoic acid, octadecanoic acid or acombination thereof. Excipient 3 in specific compositions isH—(O—CH₂—CH₂)_(n)—OH where n is an integer from 3 to 900 (e.g., PEGhaving an average molecular weight in the range of 2000-12000).Excipient 4 in specific compositions is(R,2S,5R)-2-isopropyl-5-methylcyclohexanol or a combination of one ormore of (1R,2S,5R)-2-isopropyl-5-methylcyclohexanol,(2S,5R)-2-Isopropyl-5-methylcyclohexanone, Acetic acid[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl] ester,1,3,3-Trimethyl-2-oxabicyclo[2,2,2]octane, and(R)-1-methyl-4-(1-methylethenyl)cyclohexene. These compositions can befilled into soft gel or hard gel capsules depending on its flowabilityat the temperatures useful for making these dosage forms.

Exemplary Compositions

Shown below are various compositions suitable for oral administration asdescribed herein. In these Examples the amount of excipient adds up to100% (does not include the API) and the API weight percent is the finalweight percent in the pharmaceutical composition.

Composition No. Component (w/w %) 28 29 30 31 32 33 34 35 36 API 23 2425 26 27 28 29 30 31 Excipient 1 40-90 45-90 50-90 55-90 40-90 45-9055-90 50-90 50-90 Excipient 2  5-15  1-15  5-15  1-15  5-15 Excipient 3 1-10  1-10  1-10  1-10 Excipient 4  0-25  0-25  0-25  0-25  0-25  0-25 0-25  0-25  0-25 Additional Qs qs qs qs qs qs Qs qs qs Excipients

The API in these compositions in specific compositions is testosteronetridecanoate, testosterone undecanoate, or a combination thereof.Alternatively, the skilled artisan understands that any othertestosterone ester or steroid, or steroid ester can be used in thesecompositions accordingly. Excipient 1 in specific compositions is(9Z)-octadec-9-enoic acid. Excipient 2 in specific compositions is acombination of mono-, di-, or tri-propane-1,2,3-triol esters ofoctadecanoic acid and hexadecanoic acid, octadecanoic acid, or acombination thereof. Excipient 3 in specific compositions isH—(O—CH₂—CH₂)_(n)—OH where n is an integer from 3 to 900 (e.g., PEGhaving an average molecular weight in the range of 2000-12000).Excipient 4 in specific compositions is(1R,2S,5R)-2-isopropyl-5-methylcyclohexanol or a combination of one ormore of (1R,2S,5R)-2-isopropyl-5-methylcyclohexanol,(2S,5R)-2-Isopropyl-5-methylcyclohexanone, Acetic acid[(1R2S,5R)-2-isopropyl-5-methylcyclohexyl] ester,1,3,3-Trimethyl-2-oxabicyclo[2,2,2]octane, and(R)-1-methyl-4-(1-methylethenyl)cyclohexene. These compositions can befilled into soft gel or hard gel capsules depending on its flowabilityat the temperatures useful for making these dosage forms.

Exemplary Compositions

Shown below are various compositions suitable for oral administration asdescribed herein. In these Examples the amount of excipient adds up to100% (does not include the API) and the API weight percent is the finalweight percent in the pharmaceutical composition.

Composition No. Component (w/w %) 37 38 39 40 41 42 43 44 45 API 23 2425 26 27 28 29 30 31 Excipient 1 45-80 45-80 45-80 45-80 45-80 45-8045-80 45-80 45-80 (e.g., Fatty acid) Excipient 2  1-15  1-15  1-15  1-15 1-15  1-15  1-15  1-15  1-15 Excipient 3  0-10  0-10  0-10  0-10  0-10 0-10  0-10  0-10  0-10 Excipient 4 0.1-0.3 0.1-0.3 0.1-0.3 0.1-0.30.1-0.3 0.1-0.3 0.1-0.3 0.1-0.3 0.1-0.3 Additional Qs qs qs qs qs qs qsQs Qs Excipients

The API in these compositions in specific compositions is testosteronetridecanoate, testosterone undecanoate, or a combination thereof.Alternatively, the skilled artisan understands that any othertestosterone ester or steroid, or steroid ester can be used in thesecompositions accordingly. Excipient 1 in specific compositions is(9Z)-octadec-9-enoic acid, hexadecanoic acid or a combination thereof.Excipient 2 in specific compositions is a combination of mono-, di-, ortri-propane-1,2,3-triol esters of octadecanoic acid and hexadecanoicacid. Excipient 3 in specific compositions polyoxylated hydrogenatedcastor oil (Cremophor R40). Excipient 4 in specific compositions isascorbyl palmitate. These compositions can be filled into soft gel orhard gel capsules depending on its flowability at the temperaturesuseful for making these dosage forms.

It is to be understood that various formulations of androgen receptoragonists, testosterone and testosterone esters can be used in themethods described herein. Such exemplary formulations can be found e.g.,US Patent Application Publication Nos. 20170354663; 20180028542;20180125787; 20180147215; 20180021349; 20170065614; 20150328233;20170136033; 20140011780; 20170056415; 20170020893; 20170246187;20180110786; and 20170106002; each of which is incorporated by referencein its entirety.

Examples of Such Formulations are as Follows:

Formulation AAA Ingredients mg/capsule (% w/w): Testosterone Undecanoate158.3 mg (19.8%); Oleic Acid 413.1 mg (51.6%); Cremophor RH 40 128.4 mg(16.1%); Borage Seed Oil 80.0 mg (10%); Peppermint Oil 20.0 mg (2.5%);BHT 0.2 mg (0.03%); Total 800 mg (100%).

Formulation AAB Ingredients mg/capsule (% w/w): Testosterone Undecanoate158.3 mg (19.8%); Oleic Acid 412.5 mg (51.6%); Cremophor RH 40 128.4 mg(16.0%); Peppermint Oil 20.0 mg (2.5%); Borage Seed Oil 80.0 mg (10%);BHT 0.2 mg (0.03%) Ascorbyl Palmitate 0.8 mg (0.1%); Total 800 mg(100%).

Thus, the formulation can comprise: (a) 15-25 percent by weight of asolubilized testosterone undecanoate; (b) 12-18 percent by weight of atleast one hydrophilic surfactant; (c) 50-65 percent by weight of atleast one lipophilic surfactant; and (d) 10-15 percent by weight of amixture of borage oil and peppermint oil.

Thus, the formulation can comprise: (a) 18-22 percent by weight of asolubilized testosterone undecanoate; (b) 15-17 percent by weight of atleast one hydrophilic surfactant; (c) 50-55 percent by weight of atleast one lipophilic surfactant; and (d) 10-15 percent by weight of amixture of borage oil and peppermint oil.

Thus, the formulation comprises: a) a phytosterol or phytosterol ester;b) a non-sterol solubilizing agent; and c) at least one lipophilic,poorly water soluble therapeutic agent (e.g., a testosterone ester suchas testosterone undecanoate or testosterone tridecanoate), in acomposition, wherein the composition is effective to enhance solubilityof at least one therapeutic agent, as compared to the solubility of thesame therapeutic agent in the absence of a) a phytosterol or phytosterolester and b) a non-sterol solubilizing agent. Exemplary formulations oftype are given in the next two tables.

Component (% as W/W) BBA BBB BBC Testosterone Undecanoate 11.54 11.5411.54 Castor oil 25.40 Oleic acid 25.93 75.93 Lipoid E PC S (EggLecithin) 0.85 0.85 0.85 Cremophor RH40 29.63 9.88 9.87 Polysorbate-8019.74 19.73 Labrafil 1944 CS 12.70 11.69 5.17 Lauroglycol 90 16.93Glyceryl mono-oleate Type 40 15.37 8.85 Precirol ® 13.26 Phytosterols asCardioAid XF 2.12 2.11 2.12 Hypromellose 2910 (HPMC) 0.85 0.85 0.85dl-α-Tocopherol 2.00 1.77 Butylated Hydroxyanisole 0.05 0.05 0.05

Formulation Formulation Formulation Component CCA CCB CCC TU 20.3%71.7%  42.2% Oleic acid 18.5% 6.7%  4.0% GMO 11.1% 4.0%  2.4% Labrafil M1944 CS  8.4% 3.1%  1.8% Cremophor RH40  7.1% 2.6%  1.5% Tween 80 14.1%5.1%  3.0% Phytosterols 18.2% 5.8% 44.6% Lyso Lecithin  0.6% 0.2%  0.1%HPMC  0.6% 0.2%  0.1% Vitamin E  1.3% 0.5%  0.3%

Some formulation of the formulations described herein include a watersoluble (hydrophilic) surfactant, anon-ionic surfactant and a waterinsoluble (hydrophobic) surfactant. The surfactants can be in any ratiothat will give the desired properties of the formulations with thetestosterone ester (e.g., testosterone undecanoate or testosteronetridecanoate). In certain embodiments of the formulations describedherein the ratio by weight of the water soluble surfactant, anon-ionicsurfactant and a water insoluble surfactant is about 4:1:1, 4:2:1,4:3:1, 4:4:1, 4:5:1, 5:1:1, 5:2:1, 5:3:1, 5:4:1 or 5:5:1. In certainembodiments of the formulations described herein the ratio by weight ofthe water soluble surfactant, anon-ionic surfactant and a waterinsoluble surfactant is about 1:1:2, 1:2:2, 1:3:2, 1:4:2, 1:5:2, 2:1:2,2:2:2, 2:3:2, 2:4:2, 2:5:2, 3:1:2, 3:2:2, 3:3:2, 3:4:2, 3:5:2, 4:1:2,4:2:2, 4:3:2, 4:4:2, 4:5:2, 5:1:2, 5:2:2, 5:3:2, 5:42 or 5:5:2. Incertain embodiments of the formulations described herein the ratio byweight of the water soluble surfactant, anon-ionic surfactant and awater insoluble surfactant is about 1:1:3, 1:2:3, 1:3:3, 1:4:3, 1:5:3,2:1:3, 2:2:3, 2:3:3, 2:4:3, 2:5:3, 3:1:3, 3:2:3, 3:3:3, 3:4:3, 3:5:3,4:1:3, 4:2:3, 4:3:3, 4:4:3, 4:5:3, 5:1:3, 5:2:3, 5:3:3, 5:4:3 or 5:5:3.In certain embodiments of the formulations described herein the ratio byweight of the water soluble surfactant, a non-ionic surfactant and awater insoluble surfactant is about 1:1:4, 1:2:4, 1:3:4, 1:4:4, 1:5:4,2:1:4, 2:2:4, 2:3:4, 2:4:4, 2:5:4, 3:1:4, 3:2:4, 3:3:4, 3:4:4, 3:5:4,4:1:4, 4:2:4, 4:3:4, 4:4:4, 4:5:4, 5:1:4, 5:2:4, 5:3:4, 5:4:4 or 5:5:4.In certain embodiments of the formulations described herein the ratio byweight of the water soluble surfactant, a non-ionic surfactant and awater insoluble surfactant is about 1:1:5, 1:2:5, 1:3:5, 1:4:5, 1:5:5,2:1:5, 2:2:5, 2:3:5, 2:4:5, 2:5:5, 3:1:5, 3:2:5, 3:3:5, 3:4:5, 3:5:5,4:1:5, 4:2:5, 4:3:5, 4:4:5, 4:5:5, 5:1:5, 5:2:5, 5:3:5, 5:4:5 or 5:5:5.In certain embodiments the ratio of by weight of the water solublesurfactant, a non-ionic surfactant and a water insoluble surfactant is1:3:5.

Examples of these types of formulation can have e.g. from 5%-30% andpreferably 5%-15% loading (w/w %) of testosterone ester (e.g.,testosterone undecanoate or testosterone tridecanoate) and FormulationXA (CAPRYOL 90/TWEEN 80/TRANSCUTOL P (2:5:5)); Formulation XB (Propyleneglycol/CREMOPHOR EL/CAPRYOL 90 (1:3:5)); Formulation XC (Sunflower SeedOil/CREMOPHOR EL/SPAN 80 (3/4/3 w/w/w)); Formulation XD (CornOil/CREMOPHOR EL/SPAN 80 (3/4/3 w/w/w)); and Formulation E (SunflowerSeed Oil/CREMOPHOR EL/Maisine (1:1:1)). Related formulation aredisclosed below (other testosterone esters can be sued includingtestosterone tridecanoate). Moreover the formulation that do not includetestosterone undecanoate below can be adapted to include testosteroneesters such as testosterone undecanoate, testosterone tridecanoate orother testosterone esters.

Testosterone Propylene Cremophor Capryol 5% Testosterone Undeca- Undeca-Formu- noate glycol EL 90 ethyl noate lation (%) (mg) (mg) (mg) oleate(mg) Total Formu- 0 116.5 354.1 529.5 — — 1000 lation B0 Formu- 9 106.0322.2 481.8 — 90.0 1000 lation B Formu-   7.5 107.7 327.5 489.7 — 75.01000 lation B1 Formu- 0 110.6 336.4 503.0 50.0 — 1000 lation H0 Formu- 9100.7 306.1 457.7 45.5 90.0 1000 lation H1 Formu-   7.5 102.3 311.2465.3 46.3 75.0 1000 lation H2

Another composition which can be used with the methods described hereinclude Andriol or Andriol Testocaps which are or were commerciallyavailable.

(a) testosterone undecanoate, (b) cholesterol, and (c) at least onephospholipid, wherein (a) and (b) are present in a weight ratio (a):(b)ranging from 1.0.0.05 to 10:0.30 and (a), (b) and (c) are present in aweight ratio of (a): ((b)+(c)) ranging from 1.0:1.0 and 1.0:2.5.

In one aspect, the phospholipid is selected from distearoylphosphatidylcholine, dipalmitoyl phosphatidylcholine, dimyristoylphosphatidylcholine, egg phosphatidylcholine, soy phosphatidylcholine,dimyristyl phosphatidyl glycerol Sodium, 1,2-dimyristoyl-phosphatidicacid, dipalmitoyl phosphatidylglycerol, dipalmitoyl phosphate,1,2-distearoyl-sn-glycero-3-phospho-rac-glycerol. 1,2-distearoylsn-glycero-3-phosphatidic acid, phosphatidylserine and sphingomyelin, ora combination thereof. In one aspect, the phospholipid is distearoylphosphatidylcholine.

An oral pharmaceutical composition comprising a testosterone derivativehaving a log P of at least 5, wherein the testosterone derivative isselected from testosterone undecanoate, testosterone enanthate,testosterone oleate, or testosterone palmitate, wherein the testosteronederivative is present in an amount from 0.5% to 20% by weight based on100% total weight of the composition, and a vehicle, wherein the vehiclecomprises (a) a fat component in an amount of at least 500 mg sufficientto achieve lymphatic absorption in a mammal, wherein the fat componentcomprises a mono-glyceride of long chain fatty acids, a tri-glyceride oflong chain fatty acids, or a mono- and triglyceride of long chain fattyacids, wherein the long chain fatty acids in the monoglycerides areselected from fatty acid chains having from 14 to 22 carbon atoms andthe long chain fatty acids in the triglycerides are selected from fattyacid chains having from 14 to 22 carbon atoms, and (b) a hydrophilicsurfactant, wherein the hydrophilic surfactant is selected fromhydrogenated castor oil ethoxylates, polysorbates or any otherhydrophilic surfactant with a Hydrophile-Lipophile Balance (HLB) valueof 10 or higher, and any combination thereof, wherein the weight ratio(a):(b) is from 10:1 to 1:1.

It is also to be understood that although this disclosure is describedmainly in the context of oral testosterone/testosterone estertreatments, other routes of administration used in the art can beadapted to the methods described in this disclosure.

The following examples are provided to promote a more clearunderstanding of certain embodiments of this disclosure and are in noway meant as a limitation thereon.

EXAMPLES Example 1: Clinical Trial

Oral testosterone therapy was evaluated in a multicenter, phase 3,randomized, open-label, active controlled, parallel-group study thatincluded a 13-week efficacy phase and a 52-week safety phase. An activearm in which subjects received T gel was included for safety evaluationonly.

Materials and Methods Study Centers and Ethics

Forty US sites enrolled subjects from February 2014 to April 2015. Eachsite received Institutional Review Board approval of the protocol beforestudy commencement.

Study Population

Males 18 through 80 years old with a documented diagnosis of primaryhypogonadism (congenital or acquired) or hypogonadotropic hypogonadism(congenital or acquired) and with morning serum T<300 ng/dL based on 2consecutive blood samples obtained between 0600 and 1000 on 2 separatedays at approximately the same time were eligible to participate.Subjects were either naïve to T therapy or completed an adequate washoutof T therapy (eg, 12 weeks after intramuscular androgen injectionsexcluding TU injections which required a longer waiting period; 4 weeksafter topical or buccal androgens; and 3 weeks after oral androgens).Exclusion criteria included abnormal prostate digital rectal examinationwith palpable nodule(s) or International Prostate Symptom Score(IPSS)>19 points; body mass index ≥38 kg/m², clinically significantlaboratory values (baseline hemoglobin <11.5 or >16.5 g/dL, hematocrit<35% or >54%, serum transaminases >2.5 times upper limit of normal,serum bilirubin >2.0 mg/dL, creatinine >2.0 mg/dL, prostate specificantigen [PSA] >2 ng/mL, prolactin >17.7 ng/mL); history of seizures orconvulsions; any surgical procedure that might interfere withgastrointestinal motility, pH, or absorption; stroke or myocardialinfarction within years; current or suspected prostate or breast cancer;severe, untreated, obstructive sleep apnea; long QT syndrome orunexplained sudden death in first-degree relative; concurrent medicationuse that could impact absorption, distribution, metabolism, or excretionof TU or place subject at risk for treatment with T; and dose changes ofantihypertensive, lipid-lowering, or hypoglycemic agents within previous3 months.

Study Design and Procedures

Subjects were randomized in a 2:1 ratio to oral testosterone undecanoateor T gel. oral testosterone undecanoate subjects started at a dose of225 mg TU (“testosterone undecanoate”) taken twice daily (total dailydose: 450 mg TU) every 12 hours. For optimal lymphatic absorption oraltestosterone undecanoate must be administered with a meal [15, 16].Therefore, subjects were instructed to administer oral testosteroneundecanoate after a standard meal (defined as a meal consisting of 800to 1400 calories with approximately 20% to 35% fat content). The oraltestosterone undecanoate dose was titrated at Weeks 4 and 8, ifnecessary, based on results of intensive 24-hour PK blood samplingobtained at Weeks 3 and 7, respectively. Oral testosterone undecanoatesubjects stayed at the clinic overnight during each intensive PK bloodsampling period. Dose titration was based on serum T averageconcentration over 24 hours (Cavg0-24 h) and maximum observed serumconcentration (Cmax) and was titrated by 75 mg dose adjustments. Oraltestosterone undecanoate dose levels permitted during the study were 150mg BID, 225 mg BID, and 300 mg BID. Data collected during an intensive24-hour PK sampling overnight stay at Week 13 were used for efficacyanalysis; dose was not adjusted at this visit. Additional outpatientvisits were conducted at Weeks 26, 39, and 52 during which single blooddraws were performed 3 to 6 hours post morning dose. Dose was notadjusted during these visits.

T gel (ANDROGEL® 1.62%, AbbVie, Chicago, Ill., US) was supplied innon-aerosol, metered dose pumps that deliver 20.25 mg T per completepump actuation. T gel was dosed according to product labeling. Subjectsreceiving T gel completed outpatient visits at Weeks 2 and 4 with singleblood draws to determine titration and at Weeks 3 and 5 for dosechanges, if necessary. They also completed an outpatient visit at Week 7for safety assessments and at Weeks 13, 26, 39 and 52 during whichsingle blood samples were obtained 3 to 6 hours after the morning dose.Dose was not adjusted during these visits. Overnight clinic stays werenot required for T gel subjects.

Assessments

Safety endpoints included adverse events (AEs), physical examinationfindings, vital signs, electrocardiograms (ECGs), and clinicallaboratory tests. AEs were classified using the Medical Dictionary forRegulatory Activities (Version 16.1). Safety endpoints were summarizedusing descriptive statistics. Lab parameters were evaluated using twosample t-tests comparing change from baseline to end of study (EOS)across oral testosterone undecanoate and T gel subjects with p-values<0.05 considered statistically significant.

Hormone Assessment and Statistical Analysis

Serum levels of T, TU, dihydrotestosterone (DHT), dihydrotestosteroneundecanoate (DHTU), and estradiol (E2) were evaluated in oraltestosterone undecanoate treated subjects. Pharmacokinetic parameterswere calculated for T Cmax and T Cavg0-24 h. Sex hormone bindingglobulin (SHBG) was evaluated in data from all subjects. Serum Tconcentrations at screening were measured using chemiluminescenceimmunoassay kits. Hormone assays for pharmacokinetic assessment wereanalyzed at PPD Bioanalytical Laboratory in Richmond, Va. Serum sampleswere analyzed for T, DHT, TU, DHTU, and E2 using a validated liquidchromatography-tandem mass spectrometry (LC-MS/MS) assay.

Subjects

Demographic characteristics were similar for oral testosteroneundecanoate and T gel subjects (Table 1). The study was completed by61.9% and 67.6% of oral testosterone undecanoate treated and T gelsubjects, respectively. Non-safety related reasons for earlydiscontinuation included lost to follow-up (6.7% and 11.4%), consentwithdrawn due to confinement or schedule conflict (6.7% and 2.9%),consent withdrawn due to reason other than confinement or schedule (4.8%and 1.9%), met Cmax or C_(avg) stopping criteria (4.3% of oraltestosterone undecanoate treated subjects and not applicable for T gelsubjects), protocol deviation (3.3% and 2.9%), lack of efficacy (2.4%and 3.8%), and subject enrolled at more than one study site (1.9% and2.9%). Table 2 presents safety-related reasons for earlydiscontinuation.

Pharmacokinetic Assessments

Efficacy and pharmacokinetic results of this study are describedelsewhere [14]. In brief, at Week 13, serum T Cavg0-24 h was between 300and 1140 ng/dL in 87.4% of LPCN 1021 subjects (95% lower bound CI:81.7%), which met predefined efficacy criteria. Week 13 Cavg0-24 h was446 ng/dL and Cmax was 1134 ng/dL. Average serum T levels remainedwithin eugonadal levels throughout the study (481±371, 543±438, and538±545 ng/dL at Weeks 26, 39, and 52, respectively). Calculated free Tlevels, were consistently within normal values, 9 to 30 ng/dL. MeasuredDHT concentrations increased as T concentrations increased, indicatingthat T converts to DHT via 5-alpha reductase activity leading to DHTpharmacokinetics that simulated those of T. Overall ratios of DHT/T fororal testosterone undecanoate treated subject based on Cavg0-24 h atWeeks 3, 7, and 13 were 0.24, 0.26, and 0.26, respectively, and based onCmax at Weeks 3, 7, and 13 were 0.16, 0.18, and 0.18, respectively,which were within the normal range for DHT/T ratio of 0.05 to 0.33.Serum E2 concentrations for oral testosterone undecanoate treatedsubjects remained within normal levels throughout Week 52 for oraltestosterone undecanoate treated subjects.

Mean SHBG levels decreased at each post-baseline visit following oraltestosterone undecanoate administration, but not T gel (FIG. 1). Thelargest decrease in oral testosterone undecanoate treated subjectsoccurred at Week 13 (change from baseline of −11.75 nmol/L), after whichSHBG levels increased slightly and remained relatively stable.

Lipoprotein-associated phospholipase A2 decreased significantly frombaseline to EOS for both oral testosterone undecanoate and T gel, butthe difference in the change from baseline between groups was notsignificant.

TABLE 1 Trial. Demographic and Baseline Characteristics Oraltestosterone undecanoate T Gel Characteristic^(a) (N = 210) (N = 105)Age, years  52.6 (10.2)  54.2 (9.4) ≤65, n (%) 190 (90.5)  96(91.4) >65, n (%)  20 (9.5)  9 (8.6) Race, n (%) Asian  3 (1.4)  3 (2.9)Black or African American  32 (15.2)  10 (9.5) White 172 (81.9)  92(87.6) Other  3 (1.4)  0 Weight, kg  97.1 (15.0)  99.2 (14.8) Height, cm177.24 (7.4) 178.76 (7.1) Body mass index, kg/m2  30.8 (3.9)  31.0 (3.9)≥30 kg/m², n (%) 118 (56.2)  67 (63.8) <30 kg/m², n (%)  92 (43.8)  38(36.2) Prior Androgen Therapy Reported prior use 108 (51.4%)  58 (55.2%)Reported no prior use 102 (48.6%)  47 (44.8%) Serum T^(b), ng/dL 205.6(66.3) 201.9 (71.9) Luteinizing hormone, IU/L  5.8 (7.3)  4.8 (4.4)Follicle stimulating hormone,  8.4 (10.3)  7.2 (7.6) IU/L ^(a)Mean (SD)except where noted otherwise. ^(b)Serum T levels for last two collectedmeasurements at baseline (n = 420 for oral testosterone undecanoatetreated subjects and n = 208 for T gel subjects).

TABLE 2 Trial. Mean (SD) Change from Baseline to End of Study inAndrogenic Parameters, Liver Enzymes and Lipid Parameters (Safety Set, N= 314) Oral testosterone P- undecanoate N = T Gel Value 210 N = 104 OralLaboratory TU vs Parameter N Mean (SD) P-Value N Mean (SD) P-Value T GelAndrogenic Parameters Hematocrit (%) 174   2.54 (3.41) <.0001 81   2.10(3.19) <.0001 0.3333 Hemoglobin (g/L) 174   7.2 (10.65) <.0001 81   6.1(10.91) <.0001 0.4624 Platelets (10⁹/L) 170   8.5 (31.34) 0.0005 81  6.3 (25.91) 0.0310 0.5824 APTT 174   0.61 (4.07) 0.0485 80   0.39(3.41) 0.3146 0.6651 Prothrombin time 175   0.31 (1.14) 0.0004 82   0.51(3.69) 0.2129 0.5132 (sec) PSA (mcg/L) 177   0.27 (0.97) 0.0002 83  0.13 (0.24) <.0001 0.1857 Liver Function Tests Alkaline phosphatase175 −4.1 (13.33) <.0001 82   0.4 (9.29) 0.6785 0.0062 (U/L) ALT (U/L)175 −3.07 (11.22) 0.0004 82 −2.76 (11.65) 0.0351 0.8358 AST (U/L) 174−1.5 (7.52) 0.0113 82 −2.2 (8.39) 0.0190 0.4684 GGT (U/L) 177 −2.0(12.50) 0.0336 83 −0.6 (11.94) 0.6736 0.3749 Bilirubin (mcmol/L) 175−0.43 (3.66) 0.1237 82 −0.57 (3.45) 0.1402 0.7709 Lipid Parameters HDLcholesterol 176 −0.14 (0.22) <.0001 82 −0.06 (0.22) 0.0178 0.0035(mmol/L) LDL cholesterol 163 −0.05 (0.66) 0.3120 75 −0.21 (0.69) 0.01030.0942 (mmol/L) Triglyceride (mmol/L) 176 −0.18 (1.14) 0.0371 82   0.12(1.43) 0.4657 0.0750 Cholesterol (mmol/L) 177 −0.24 (0.82) 0.0001 83−0.21 (0.89) 0.0325 0.8001 Other C-Reactive Protein 166 −4.68 (30.94)0.3098 82 −7.55 (55.31) 0.1893 0.6009 (nmol/L)^(a) Lp-PLA2 (ng/mL) 179−9.6 (42.07) 0.0044 78 −13.0 (49.54) 0.0233 0.5774 ^(a)Subjects with CRPvalues >95.23 were excluded. ALT = alanine aminotransferase, APTT =activated partial thrombplastin time, AST = aspartate aminotransferase,GGT = gamma-glutamyl transferase HDL = high density lipoprotein, LDL =low density lipoprotein, Lp-PLA2 = lipoprotein-associated phospholipaseA2, PSA = prostate specific antigen

Mean hematocrit increase from baseline to EOS was similar fortreatments. To minimize excessive hematocrit increases, investigatorscould prematurely withdraw subjects with hematocrit >54%. Elevatedhematocrit (>54%) occurred in 8 oral TU treated subjects and 1 T gelsubject: 3 of these 8 oral TU treated subjects (1.4%) and the T gelsubject (1.0%) were withdrawn; 3 oral TU treated subjects were notwithdrawn because hematocrit levels decreased at a subsequent laboratoryevaluation; and 2 subjects were withdrawn due to reasons other thanelevated hematocrit. Small and similar increases in hemoglobin frompretreatment to EOS occurred in oral TU and T gel subjects.

Serum HDL cholesterol showed a significantly larger decrease at EOS fororal testosterone undecanoate than T gel. For HDL cholesterol, 19.0% oforal testosterone undecanoate subjects and 14.5% of T gel subjects had ashift from normal at baseline to low at EOS. No statisticallysignificant differences between oral testosterone undecanoate and T gelwere found between treatments for other lipid parameters.

Oral Testosterone Undecanoate Trial Results—Liver Function Enzymes andLipids Analysis

TABLE 3 Trial. Mean change from baseline of liver function enzymes for4^(th) quartile patients based on lab parameter level in 1 year oraltestosterone undecanoate study Normal Mean range Mean change Lab forchange from function the # of Mean Baseline from baseline, Enzymes studypatients baseline range baseline % Albumin 35-55 31 49.4 47-53 −2.5 −3.1% (g/L) AST (U/L) 10-43 52 35.1 27.5-86   −6.3 −16.6% ALT (U/L)10-40 51 51.1 37-85 −10.0 −16.7% ALP (U/L)  43-115 52 97.6 83.5-132 −10.2 −10.4% GGT (U/L) 10-49 52 70.7 39.5-393  −7.0  −7.4% Bilirubin0.1-1.0 50 0.78 0.55-1.88 −0.18 −20.5% (mg/dL) Creatinine 0.7-1.4 59 1.21.1-1.7 0.01    0.8% (mg/dL)

TABLE 4 Trial. Mean Change from Baseline of lipids for 4^(th) quartilepatients based on lab parameter level in 1 Year Oral TU Study NormalMean range Mean change for change from the # of Mean Baseline frombaseline, Lipids study patients baseline range baseline % Triglycerides 45-200 52 360.2  238-1171 −85.1 −19.0% (mg/dL) Total 125-200 52 247.0222-302 −20.2  −7.9% Cholesterol (mg/dL) LDL-C  50-160 48 154.4 133-193−10.2  −6.1% (mg/dL) Non-HDL-C N/A 51 197.6 171-258 −18.2  −8.7% (mg/dL)Lp-PLA2 <235 43 256.3 220-363 −47.8 −17.1% (ng/mL)

Example 2: Clinical Trial

The following study was designed and performed to evaluate twice-dailydosing of 225 mg TU in a population of male subjects having testosteronedeficiency. This trial was conducted in a manner similar to that ofExample 1.

All subjects received 225 mg TU BID (two capsules of 112.5 mg) takentwice daily (total daily dose of 450 mg taken as 225 mg in the morningand 225 mg in the evening), approximately 12 hours apart, approximately30 minutes after morning and evening meals, with water.

Labs were collected at baseline and end of study. Subjects were dosedfor 24 days. In the Figure legends, this trial is referred to as“16-002”.

Example 3: Clinical Trial

The following study was designed and performed to evaluate thrice-dailydosing of 150 mg TU (450 mg TU per day) in a population of male subjectshaving testosterone deficiency. This trial was conducted in a mannersimilar to that of Example 1.

All subjects received 150 mg TU BID (two capsules of 75 mg) taken thrice(total daily dose of 450 mg taken as 150 mg after breakfast, 150 mgafter lunch and 150 mg after dinner approximately 30 minutes aftermeals, with water.

Labs were collected at baseline and end of study. Subjects were dosedfor 24 days. In the Figure legends to this trial is referred to as“16-003”.

Example 4: Clinical Trial

This was a multi-center, open-label, randomized, parallel, 2-period,multiple-dose study that evaluated the safety, tolerability, and PK oforal testosterone tridecanoate in 5 groups of hypogonadal males. Period1 and Period 2 each include an up to 28-day Screening Period, a 14-dayTreatment Period, and an Exit Evaluation performed following the finalPK blood sample collection.

In Period 1, 3 groups of approximately 12 hypogonadal male subjects each(approximately 36 subjects total) were randomized to receiveadministration of either Treatment A (500 mg oral testosteronetridecanoate), Treatment B (750 mg oral testosterone tridecanoate), orTreatment C (1000 mg oral testosterone tridecanoate) once daily (QD) for14 days following standardized meals. Following completion of Period 1,the appropriate dose of oral testosterone tridecanoate for Treatment D(either 250 mg or 1250 mg oral testosterone tridecanoate) in Period 2was determined based on an evaluation of Period 1 data. Subjects whocompleted Period 1 proceeded to Period 2 following a 2-day washout.

In Period 2, two groups of approximately 12 hypogonadal male subjectseach (approximately 24 subjects total) will be randomized to receiveadministration of either Treatment D (250 mg or 1250 mg oraltestosterone tridecanoate) QD for 14 days following standardized meals,or Treatment E (500 mg oral testosterone tridecanoate) twice daily (BID)for 14 days following standardized meals.

Each subject in Period 1 or Period 2 underwent 3 overnight clinicconfinements (on Day 1, Day 8, and Day 14). Subjects entered the clinicat least 2 hours prior to the anticipated morning dosing and remained inconfinement for 24 hours after the morning dose. During this time,subjects received each assigned dose of oral testosterone tridecanoate,30 minutes (plus/minus 5 minutes) after starting a standardized meal.Blood samples for PK analysis were collected at regular intervals for 24hours after the morning dose. Following the Hour 24 blood draw, subjectswere discharged from the clinic. At the end of the Day 1 and Day 8clinic confinements, subjects received a sufficient quantity of oraltestosterone tridecanoate to administer their assigned treatment at homeuntil the next confinement. Subjects also received specific instructionson the standardized meals (approximate composition and/or example mealsfrom various restaurants and instructions for preparation of meals) tobe consumed approximately 30 minutes prior to oral testosteronetridecanoate administration, at approximately the same-time of day asthe administration during confinement.

In addition to the 3 confinements, subjects in Period 1 returned to theclinic on the morning of Day 6, Day 7, Day 12, and Day 13 for a singlepre-dose blood sample collection.

The total number of subjects planned for Period 1 of this study isapproximately 36; approximately 24 of these subjects are expected tocontinue participation into Period 2. If this is not the case,additional subjects are enrolled for Period 2 at the discretion of theSponsor.

The maximum treatment duration for a subject who participates in bothtreatment periods will be 28 days (i.e., 14 days for each period). Themaximum duration of subject participation depended on the number of daysbetween the end of Period 1 and the beginning of Period 2. This isintended to be less than or equal to 30 days; however, subjects will beinformed at the time of consent that this duration may extend beyond 30days. Assuming 30 days between periods, the maximum duration of subjectparticipation is 86 days (i.e., up to 28 days for screening, 14 days forPeriod 1, 30 days between periods, and 14 days for Period 2). In theFigure legends this trial is referred to as “1111” or “1111 QD”.

Example 5: Pharmaceutical Composition, Formulations and Unit DosageForms

The API in this example in specific compositions is testosteronetridecanoate, testosterone undecanoate, or a combination thereof.Alternatively, the skilled artisan understands that any othertestosterone ester or steroid, or steroid ester can be used in thiscompositions accordingly.

These compositions can be made by any suitable method and filled intohard gel or soft gel capsules as appropriate. For example, the one ormore of the ingredients are warmed or heated to a temperature thatallows for dissolving any solid ingredients, the API is added and mixeduntil a homogenous mixture is obtained, and the capsule can be filled atan appropriate temperature and if needed, allowed to cool to roomtemperature.

Composition (A) Quantity Fill Material per Hard Gel Capsule IngredientName % w/w Mg API 13%-16% 100-120 Glyceryl Monolinoleate, NF 58%-68%440-490 Polyoxyl 40 Hydrogenated  0%-19%  0-125 Castor Oil, NF AscorbylPalmitate, NF 0.1%-0.3% 0.5-2.5 Polyethylene Glycol 8000, NF 3%-9% 35-55Total 100.0 733.3

Composition (B) Quantity Fill Material per Hard Shell Capsule IngredientName % w/w Mg API 23%-28% 160-200 Oleic Acid, NF 60%-70% 450-530((9Z)-Octadec-9-enoic acid) Polyoxyl 40 Hydrogenated 0%-7%  0-37 CastorOil, NF Ascorbyl Palmitate, NF 0.1%-0.3% 0.5-2.5 Polyethylene Glycol8000, NF 3%-9% 35-55 Total 100.0 750.0

Composition (C) Quantity Fill Quantity Fill Material per Hard Materialper Softgel Gel Capsule Capsule Ingredient Name % w/w mg mg API 23%-28%160-205 304-390 Oleic Acid, NF 37%-46% 280-330 532-627((9Z)-Octadec-9-enoic acid) Peppermint Oil, NF 15-21 120-150 228-285Polyoxyl 40 Hydrogenated    0-7%  0-35  0-67 Castor Oil, NF AscorbylPalmitate, NF 0.20 0.5-2.5 1.0-4.8 Glyceryl Palmitostearate  9%-15% 80-100 152-190 (Glyceryl Distearate, NF) Total 100.0 750.0 1250

Composition (D) Quantity Fill Quantity Fill Material per Hard MaterialSoftgel Gel Capsule Capsule Ingredient Name % w/w mg mg API 25%-32%160-205 304-390 Oleic Acid, NF 50%-60% 340-400 646-760((9Z)-Octadec-9-enoic acid) Polyoxyl 40 Hydrogenated 0%-7% 21-32  0-61Castor Oil, NF Stearic Acid, NF 0%-7%  0-32  0-61 GlycerylPalmitostearate  3%-13% 47-58  89-110 (Glyceryl Distearate, NF; PrecirolATO 5) Ascorbyl Palmitate, NF 0.1%-3%   0.5-2.5 1.0-4.8 Total 100.00654.60 1250

Composition (E) Quantity Fill Material per Hard Gel Capsule IngredientName % w/w Mg API 27%-33% 160-205 Oleic Acid, NF ((9Z)- 50%-70% 335-395Octadec-9-enoic acid) Polyoxyl 40 Hydrogenated 0%-7%  0-30 Castor Oil,NF Ascorbyl Palmitate, NF 0.1%-0.3% 0.5-2.5 Polyethylene Glycol 3%-9%32-42 8000, NF Total 100.0 611

Example 7: Pharmaceutical Composition, Formulations and Unit DosageForms

The API in this example in specific compositions is testosteronetridecanoate, testosterone undecanoate, or a combination thereof.Alternatively, the skilled artisan understands that any othertestosterone ester or steroid, or steroid ester can be used in thiscompositions accordingly.

These compositions can be made by any suitable method and filled intohard gel or soft gel capsules as appropriate. For example, the one ormore of the ingredients are warmed or heated to a temperature thatallows for dissolving any solid ingredients, the API is added and mixeduntil a homogenous mixture is obtained and the capsule can be filled atan appropriate temperature and if needed, allowed to cool to roomtemperature.

Composition (F) Weight Percent Quantity of Fill Fill MaterialPharmaceutical per Hard Composition Gel Capsule (±1%) (±1%) IngredientName % w/w Mg API 15 110 Glyceryl 63 463 Monolinoleate, NF Polyoxyl 4015 114 Hydrogenated Castor Oil, NF Ascorbyl Palmitate, 0.2 1.5 NFPolyethylene Glycol 6 44 8000, NF Total 100 733.3

Composition (G) Weight Percent Quantity of Fill Fill MaterialPharmaceutical per Hard Composition Gel Capsule (±1%) (±1%) IngredientName % w/w mg API 24 183 Oleic Acid, NF 65 490 ((9Z)-Octadec-9-enoicacid) Polyoxyl 40 Hydrogenated 4 30 Castor Oil, NF Ascorbyl Palmitate,NF 0.2 1.5 Polyethylene Glycol 8000, 6 45 NF Total 100 750

Composition (H) Weight Percent Quantity Fill Quantity Fill of FillMaterial per Material Pharmaceutical Hard Gel per Softgel CompositionCapsule Capsule (±1%) (±1%) (±1%) Ingredient Name % w/w Mg mg API 24 183300 Oleic Acid, NF ((9Z)-Octadec-9-enoic 41 308 513 acid) PeppermintOil, NF 18 136 225 Polyoxyl 40 4 30 50 Hydrogenated Castor Oil, NFAscorbyl Palmitate, NF 0.2 1.5 2.5 Glyceryl Palmitostearate 12 90 150(Glyceryl Distearate, NF) Total 100 750 1241

Composition (I) Weight Percent Quantity Fill Quantity Fill of FillMaterial per Material Pharmaceutical Hard Gel per Soft CompositionCapsule Gel Capsule (±1%) (±1%) (±1%) Ingredient Name % w/w Mg mg API 28183 350 Oleic Acid, NF 55 365 688 ((9Z)-Octadec-9- enoic acid) Polyoxyl40 4 26 50 Hydrogenated Castor Oil, NF Stearic Acid, NF 4 26 50 Glyceryl8 52 100 Palmitostearate (Glyceryl Distearate, NF; Precirol ATO 5)Ascorbyl Palmitate, 0.2 1.3 2.5 NF Total 100 654 1241

Composition (J) Weight Percent of Quantity Fill Fill PharmaceuticalMaterial Composition per Hard Gel (±1%) Capsule (±1%) Ingredient Name %w/w mg API 30 183 Oleic Acid, NF 59 365 ((9Z)-Octadec-9- enoic acid)Polyoxyl 40 4 24 Hydrogenated Castor Oil, NF Ascorbyl Palmitate, 0.2 1.2NF Polyethylene 6 36 Glycol 8000, NF Total 100 611

Based on the description provided herein and the results of the clinicaltrial, it is now possible to provide pharmaceutical compositions similarto those described as Compositions (A)-(J) having API The API in thisexample in specific compositions is testosterone tridecanoate,testosterone undecanoate, or a combination thereof (alternatively, theskilled artisan understands that any other testosterone ester orsteroid, or steroid ester can be used in this compositions accordingly)in an amount of e.g., 1 mg to 10 mg, 10 mg to 25 mg, 25 mg to 50 mg, 75mg to 100 mg, 100 mg to 125 mg, 125 mg to 150 mg, 150 mg to 175 mg, 175mg to 200 mg, 200 mg to 225 mg, 225 mg to 250 mg, 250 mg to 275 mg, 275mg to 300 mg, 300 mg to 325 mg, 325 mg to 350 mg, 350 mg to 375 mg, 375mg to 400 mg, 400 mg to 425 mg, 425 mg to 450 mg, 450 mg to 475 mg, 475mg to 500 mg, 525 mg to 550 mg, 550 mg to 575 mg, or 575 mg to 600 mg.

Other formulation for use in the method include, but are not limited toFormulation XX1 Ingredients mg capsule %, w/w Testosterone Undecanoate158.3 mg (19.8 w/w %) Oleic Acid 413.1 mg (51.6%) Cremophor RH 40 128.4mg (16.1 w/w %) Borage Seed Oil 80.0 mg (10 w/w %) Peppermint Oil 20.0mg (2.5%) BHT 0.2 mg (0.03 w/w %) Total 800 mg (100 w/w %) and XX2Ingredients mg/capsule w/w %, Testosterone Undecanoate 158.3 mg (19.8%)Oleic Acid 412.5 mg (51.6% w/w) Cremophor RH 40 128.4 mg (16.0 w/w %)Peppermint Oil 20.0 mg (2.5 w/w %) Borage Seed Oil 80.0 mg (10% w/w)0.03% w/w BHT Ascorbyl Palmitate 0.8 mg (0.1% w/w) Total 800 mg (100%w/w).

Similar composition to any specific compositions describe herein canalso have for example:

-   -   (a) a different fatty acid, an additional fatty acid or a both,    -   (b) a different hydrophilic surfactant, an additional        hydrophilic surfactant or both,    -   (c) a mono- or di-glyceride in place of the fatty acid or in        combination with the fatty acid,    -   (d) a different solidifying agent, an additional solidifying        agent, or both,    -   (e) a different diglyceride than glyceryl palmitostearate, an        additional diglyceride or both,    -   (f) a different antioxidant, an additional antioxidant or both,    -   (g) have additional additives,    -   (h) use menthol or another alcohol in place of or in addition to        peppermint oil,    -   (i) use a tocopherol in place of fatty acid, in combination with        fatty acid, in place of peppermint oil, in addition to        peppermint oil or a combination thereof,    -   (j) use a different monoglyceride than glyceryl monolinoleate,        an additional monoglyceride, a diglyceride in place of glyceryl        monolinoleate, a diglyceride in combination with glyceryl        monolinoleate or a combination thereof, or (k) a combination of        any of the above.

Moreover, it is noted that any of the formulations disclosed herein caninclude Vitamin E (e.g., tocopherol), Vitamin E derivatives, Vitamin Eprodrugs, Omega-3 fatty acids and the such by adjusting the relativeamounts of the other formulation components to achieve the desiredformulation.

Theoretical Qty. per Capsule Ingredients Name % w/w TestosteroneUndecanoate  5-40 (or testosterone ester) Oleic Acid, NF 30-70 Polyoxyl35 Castor Oil, NF  0-10 Stearic Acid, NF  0-10 Glyceryl Palmitostearate 0-20 (Glyceryl Distearate, NF; Precirol ATO 5) Ascorbyl Palmitate, NF0-5 Total 100.0

1144-06 Formula

Theoretical Qty. per Capsule Ingredients Name % w/w TestosteroneUndecanoate  5-40 (or testosterone ester) Vitamin E Acetate, USP 10-60Oleic Acid, NF  0-50 Polyoxyl 35 Castor Oil, NF  0-20 Stearic Acid, NF 0-10 Glyceryl Palmitostearate  0-20 (Glyceryl Distearate, NF; PrecirolATO 5) Ascorbyl Palmitate, NF 0-5 Total 100.0

Other tocopherols, tocotrienols and the such can be sued in thisformulations such as d-alpha tocopherol or its acetate as describedelsewhere herein.

Example 6: Clinical Study

This example is part of an ongoing Liver Fat Study which is anopen-label, multi-center, single arm study evaluating LPCN 1144treatment (e.g., androgen therapy, testosterone therapy, oraltestosterone ester, or 225 mg testosterone undecanoate orally) in acohort of 36 hypogonadal males (NCT03868059). Subjects with at least 10%baseline liver fat were evaluated which is indicative of subjects withNAFLD with the potential to have NASH. Interim results of seven of thenine subjects in the Liver Fat Study with baseline liver fat of at least10% are presented as two subjects were unable to schedule an eight-weekMRI-PDFF visit. Baseline mean liver fat of these seven subjects was21.0%.

Baseline Results

An MRI-PDFF study of 36 male hypogonadal subjects (having 2 morningtestosterone levels of 300 ng/dL or less) was performed as part of anongoing trial. Basic baseline labs including liver function tests (e.g.,AST & ALT) and serum triglycerides were collected and analyzed. It wasfound by non-linear regression, that BMI (ALT, AST, serum Triglyceride)was associated with liver fat (P<0.006). It was found by non-linearregression, that serum triglyceride levels (obesity, hypertension, type2 diabetes) were associated with liver fat (P<0.006). The analysis ofthis data is summarized in the figures.

Interim Results

Treatment results showed an absolute mean reduction from baseline of7.6% liver fat and demonstrated a 38% relative mean liver fat reductionfrom baseline. Moreover, there was an 86% responder rate in whichsubjects experienced at least a 4.1% absolute reduction in liver fatfrom baseline and a 71% responder rate in which subjects experienced atleast a 29% reduction in liver fat from baseline.

End of Study Results

34 subjects were evaluable at end-of-study. 21 subjects had NAFLD atbaseline (liver fat greater than or equal to 5%, mean liver fat=12.1%),10 subjects had greater than 8% liver fat at baseline (mean=12.1%), and8 subjects had greater than 10% liver fat at baseline (mean=20.5%). Meanrelative liver fat % change after 16 weeks of treatment was −33% forsubjects having NAFLD (e.g., baseline liver fat of 5% or greater), −42%for baseline liver fat of 8% or greater, and −40% for baseline liver fatof 10% or greater. The responder rates (% of patients with at least a30% relative reduction in liver fat from baseline) was 71% for greaterthan or equal to 5% baseline liver fat, 80% for greater than or equal to8% baseline liver fat, and 70% for greater than or equal to 10% baselineliver fat. NAFLD was resolved (baseline liver fat greater than or equalto 5% going to less than 5% at end of study) in 48% of subject. 100% ofsubjects with above normal ALT levels (mean baseline=48.7) ended thestudy with normal ALT levels. %0% of subjects with above normal GGTlevels ended the study with normal GGT levels. 60% of subjects had BUNnormalization. The normalization rates for total cholesterol, LDL-C,triglyceride were 29%, 50% and 21% respectively. The mean relative liverfat change is patients with NAFLD resolution was −55%. As the durationof therapy increased from 8 weeks to 16 weeks, liver fat reductions wereimproved as well as the percent of subject achieving NAFLD resolution.

A recent publication in Therapeutic Advances in Gastroenterology (Patelet al., Therapeutic Advances in Gastroenterol. 2016 September; 9(5):692-701) quantified the magnitude of MRI-PDFF reduction corresponding toa histologic response in NASH in a clinical setting with paired liverbiopsy. The results concluded that histologic responders had astatistically significant reduction in MRI-PDFF of −4.1% with a meanrelative percent change of −29.3%.

This is a particularly surprising and unexpected finding since oraltestosterone undecanoate lowers serum SHBG levels—the skilled artisanwould expect that lower SHBG would be expected to result in greaterliver fat according the art.

Thus, the skilled artisan can apply these teaching and examples toemploy androgen therapy for treating or preventing liver disease asdescribed herein.

It is understood that the above-described various types of compositions,dosage forms and/or modes of applications are only illustrative ofpreferred embodiments of the present invention. Numerous modificationsand alternative arrangements may be devised by those skilled in the artwithout departing from the spirit and scope of the present invention andthe appended claims are intended to cover such modifications andarrangements. Thus, while the present invention has been described abovewith particularity and detail in connection with what is presentlydeemed to be the most practical and preferred embodiments of theinvention, it will be apparent to those of ordinary skill in the artthat variations including, but not limited to, variations in size,materials, shape, form, function and manner of operation, assembly anduse may be made without departing from the principles and concepts setforth herein.

What is claimed is:
 1. A pharmaceutical composition for treating atleast one of NASH, NASH post-liver transplantation, hepatitis, alcoholicsteatohepatitis, viral steatohepatitis, genetic steatohepatitis,non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liverdisease, viral fatty liver disease, genetic fatty liver disease, and asymptom thereof, comprising at least one of a testosterone, atestosterone ester, a testosterone ester and tocopherol (TET) or atocopherol derivative, and a combination thereof.
 2. The pharmaceuticalcomposition of claim 1, wherein said pharmaceutical composition treatsat least one co-morbid condition of obesity, type 2 diabetes,dyslipidemia, cardiovascular disease, thyroid dysfunction, chronickidney disease, liver disease, osteoporosis, hypogonadism, hypertension,sarcopenia, and cachexia.
 3. The pharmaceutical composition of claim 1,wherein said at least one of a testosterone ester comprises at least oneof testosterone undecanoate (TU), testosterone dodecanoate (TD), andtestosterone tridecanoate (TT).
 4. The pharmaceutical composition ofclaim 3, wherein said at least one testosterone ester is administeredwith at least one pharmaceutical agent of metformin, glibenclamide,gliclazide, rosiglitazone, pioglitazone, troglitazone, acarbose,miglitol, nateglinide, repaglinide, exenatide, sitagliptin, pramlintide,atorvastatin, rosuvastatin, simvastatin, pravastatin, lovastatin,fluvastatin, pitavastatin, butanoic acid, CER209, evogliptin, DUR928,MK-4074, OPRX-106, PF06865571, PF06882961, PXS-5382A, RG-125, RYI-018,seladelpar, SGM-1019, aramchol, ARX618, BI 1467335, DS102, EDP-305,Emricasan, gemcabene, GR-MD-02, GRI-0621, GS-0976, GS-9674, IMM-124E,IONIS-DGAT2Rx, IVA-337, Lipaglyn, LJN452, LMB763, MGL-3196, MN-001,MSDC-0602K, NC101, NGM282, NS-0200, Ozempic, PF-05221304, PF-06835919,remogliflozin etabonate, SHP626, TVB-2640, VK2809, cenicriviroc,elafibranor, ocaliva (obeticholic acid), selonsertib, and a combinationthereof.
 5. The pharmaceutical composition of claim 1, wherein if saidpharmaceutical composition comprises a single testosterone ester,loading of said single testosterone ester per unit dosage form of saidpharmaceutical composition comprises at least one of 1-50% w/w, 5-30%w/w, 10-30% w/w, and 5-15% w/w.
 6. The pharmaceutical composition ofclaim 1, wherein if said pharmaceutical composition comprises aplurality of testosterone esters and includes TU, loading of said TU perunit dosage form of said pharmaceutical composition comprises at leastone of 1-50% w/w, 5-30% w/w, 10-30% w/w, and 5-15% w/w, and wherein ifsaid pharmaceutical composition comprises a plurality of testosteroneesters and includes TD, loading of said TD per unit dosage form of saidpharmaceutical composition comprises at least one of 1-50% w/w, 5-30%w/w, 10-30% w/w, and 5-15% w/w, and wherein if said pharmaceuticalcomposition comprises a plurality of testosterone esters and includesTT, loading of said TT per unit dosage form of said pharmaceuticalcomposition comprises at least one of 1-50% w/w, 5-30% w/w, 10-30% w/w,and 5-15% w/w.
 7. The pharmaceutical composition of claim 1, wherein ifsaid pharmaceutical composition is prepared for a male subject andcomprises TU, daily dosage of said TU comprises at least one of 10 mg to1,000 mg, 200 mg to 750 mg, and 300 mg to 600 mg, and wherein if saidpharmaceutical composition is prepared for a male subject and comprisesTD, daily dosage of said TD comprises 10 mg to 1,000 mg, and wherein ifsaid pharmaceutical composition is prepared for a male subject andcomprises TT, daily dosage of said TT comprises at least one of 10 mg to1,000 mg, 400 mg to 2,000 mg, and 600 mg to 1,800 mg, and wherein ifsaid pharmaceutical composition is prepared for a female subject andcomprises TU, daily dosage of said TU comprises 1/10th- 1/15th of atleast one of 10 mg to 1,000 mg, 200 mg to 750 mg, and 300 mg to 600 mg,and wherein if said pharmaceutical composition is prepared for a femalesubject and comprises TD, daily dosage of said TD comprises 1/10th-1/15th of 10 mg to 1,000 mg, and wherein if said pharmaceuticalcomposition is prepared for a female subject and comprises TT, dailydosage of said TT comprises 1/10th- 1/15th of at least one of 10 mg to1,000 mg, 400 mg to 2,000 mg, and 600 mg to 1,800 mg.
 8. Thepharmaceutical composition of claim 1, wherein in response toadministration of said pharmaceutical composition to a male subjecthaving a testosterone concentration baseline below at least one of 350ng/dL, 300 ng/dL, 250 ng/dL, 200 ng/dL, 150 ng/dL, and 100 ng/dL, saidtestosterone concentration (C_(ave0-24)) of said male subject isincreased over said subject's baseline.
 9. The pharmaceuticalcomposition of claim 8, wherein said testosterone concentration(C_(ave0-24)) increase comprises an increase of at least one of 30, 50,75, 100, 150, 200, 300, 400 or 500 ng/dL.
 10. The pharmaceuticalcomposition of claim 1, wherein said pharmaceutical compositioncomprises at least one pharmaceutically acceptable carrier.
 11. Thepharmaceutical composition of claim 1, wherein said pharmaceuticalcomposition comprises at least one of a hydrophilic carrier, alipophilic carrier, and an additive.
 12. The pharmaceutical compositionof claim 11, wherein said hydrophilic carrier comprises at least one ofa polyoxylated mono-glyceride, a polyoxylated di-glyceride, apolyoxylated tri-glyceride, a polyoxylated vegetable oil, a polyoxylatedhydrogenated vegetable oil, a polyoxylated mono-fatty acid, apolyoxylated di-fatty acid, a polyoxylated tri-fatty acid, ahydrogenated vegetable oil, Cremophor, Span, Tween, SLS, Poloxamer,Polymer, and a combination thereof.
 13. The pharmaceutical compositionof claim 12, wherein said hydrogenated vegetable oil comprises at leastone of hydrogenated castor oil, hydrogenated coconut oil, hydrogenatedcottonseed oil, hydrogenated palm oil, hydrogenated soybean oil, and acombination thereof.
 14. The pharmaceutical composition of claim 12,wherein said polyoxylated hydrogenated vegetable oil comprises at leastone of polyoxylated 35 hydrogenated castor oil, polyoxylated 40hydrogenated castor oil and polyoxylated 60 hydrogenated castor oil, anda combination thereof, and wherein said Tween comprises at least one ofTween-20, Tween-21, Tween-40, Tween-60, Tween-61, Tween-65, Tween-80,Tween-81, Tween-85, Tween-120, and a combination thereof.
 15. Thepharmaceutical composition of claim 11, wherein said lipophilic carriercomprises at least one of a vegetable oil, a fatty acid, a fattyalcohol, a mono-glyceride, a di-glyceride, a tri-glyceride, ahydrogenated vegetable oil, a Vitamin E compound, polyoxylated fattyacid, polyoxylated triglyceride, polyoxylated vegetable oil, glycerylfatty acid, propylene glycol fatty acid, a PEG sorbitan fatty acid, anomega-3 fatty acid, a PEG glycol alkyl ether, a polyglycerized fattyacid, and a combination thereof.
 16. The pharmaceutical composition ofclaim 15, wherein said vegetable oil comprises at least one of castoroil, coconut oil, borage oil, cottonseed oil, peppermint oil, corn oil,peanut oil, linseed oil, olive oil, palm oil, sesame oil, soybean oil,and a combination thereof.
 17. The pharmaceutical composition of claim15, wherein said fatty acid comprises at least one of caprylic acid,capric acid, lauric acid, palmitic acid, stearic acid, arachidic acid,behenic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleicacid, elaidic acid, vaccenic acid, linoleic acid, linoelaidic acid, anda combination thereof, and wherein said omega-3 fatty acid comprises atleast one of omega-3 EPA, omega-3 DHA, and a combination thereof. 18.The pharmaceutical composition of claim 15, wherein said hydrogenatedvegetable oil comprises at least one of hydrogenated castor oil,hydrogenated coconut oil, hydrogeneated cottonseed oil, hydrogenatedpalm oil, hydrogenated soybean oil, and a combination thereof.
 19. Thepharmaceutical composition of claim 15, wherein said glyceryl fatty acidcomprises at least one of glyceryl stearate, glyceryl oleate, glycerylcaprate, glyceryl caprylate, glyceryl laurate, glyceryl stearate,glyceryl palmitate, glyceryl linoleate, glyceryl myristate, and acombination thereof, and wherein said propylene glyceryl fatty acidcomprises at least one of propylene glyceryl stearate, propyleneglyceryl oleate, propylene glyceryl caprate, propylene glycerylcaprylate, propylene glyceryl laurate, propylene glyceryl stearate,propylene glyceryl palmitate, propylene glyceryl ricinoleate, propyleneglyceryl myristate, and a combination thereof.
 20. The pharmaceuticalcomposition of claim 19, wherein said glyceryl fatty acid comprises atleast one of a glyceryl mono-fatty acid, a glyceryl di-fatty acid, and aglyceryl tri-fatty acid, and wherein said propylene glyceryl fatty acidcomprises at least one of a propylene glyceryl mono-fatty acid, apropylene glyceryl di-fatty acid, and a propylene glyceryl tri-fattyacid.
 21. A Method of treating at least one of NASH and a symptomthereof in a subject in need of treatment thereof comprising orallyadministering to said subject a pharmaceutical composition resulting ina therapeutically effective testosterone concentration in said subject.22. The method of claim 21, wherein said method further includesadministering a therapeutically effective amount of a combination ofandrogen receptor agonists to said subject.
 23. The method of claim 22,wherein said androgen receptor agonists comprise at least one of atestosterone, a testosterone ester, a testosterone ester and tocopherol(TET) or a tocopherol derivative, and a combination thereof.
 24. Themethod of claim 23, wherein said at least one of a testosterone ester isadministered with at least one pharmaceutical agent of metformin,glibenclamide, gliclazide, rosiglitazone, pioglitazone, troglitazone,acarbose, miglitol, nateglinide, repaglinide, exenatide, sitagliptin,pramlintide, atorvastatin, rosuvastatin, simvastatin, pravastatin,lovastatin, fluvastatin, pitavastatin, butanoic acid, CER209,evogliptin, DUR928, MK-4074, OPRX-106, PF06865571, PF06882961,PXS-5382A, RG-125, RYI-018, seladelpar, SGM-1019, aramchol, ARX618, BI1467335, DS102, EDP-305, Emricasan, gemcabene, GR-MD-02, GRI-0621,GS-0976, GS-9674, IMM-124E, IONIS-DGAT2Rx, IVA-337, Lipaglyn, LJN452,LMB763, MGL-3196, MN-001, MSDC-0602K, NC101, NGM282, NS-0200, Ozempic,PF-05221304, PF-06835919, remogliflozin etabonate, SHP626, TVB-2640,VK2809, cenicriviroc, elafibranor, ocaliva (obeticholic acid),selonsertib, and a combination thereof
 25. The method of claim 21,wherein said subject has at least one co-morbid condition selected fromobesity, type 2 diabetes, dyslipidemia, cardiovascular disease, thyroiddysfunction, chronic kidney disease, liver disease, osteoporosis,hypogonadism, hypertension, sarcopenia, and cachexia.
 26. The method ofclaim 21, wherein said subject comprises at least one of apost-transplantation subject, pending transplantation subject, atransplantation rejection subject, and a combination thereof.
 27. Themethod of claim 21, wherein said treatment results in improvement oramelioration of changes in body composition, muscle mass, appendicularlean mass, total lean mass, fat mass, high VAT (visceral adipose fat),waist circumference, weight gain, BMI, mobility/frailty, hand gripstrength, liver frailty index, balance, and chair stand ability, and apatient reported outcome (PRO).
 28. The method of claim 27, wherein saidPRO comprises at least one of a functional status of patient-COA-symptomonly known to said patient, a quality of life (QOL) assessed by CLDQ, aperceived HRQoL score, depression, degree of mobility, sexualdysfunction, and FIS fatigue questionnaire.
 29. The method of claim 21,wherein said treatment results in improvement or amelioration of atleast one biomarker comprising a liver injury marker,lipoprotein-associated phospholipase A2, triglyceride, LDL, totalcholesterol, cholesterol, hematocrit, hemoglobin, albumin, VLDL,non-HDL, SHBG, an imaging biomarker, liver stiffness, liver biopsy,inflammation, fibrosis, bilirubin, and a liver histology biomarker. 30.The method of claim 29, wherein said liver injury marker comprises atleast one of ALT, AST, ALP, and GGT, and wherein said fibrosis biomarkercomprises at least one of CK18, AST/ALT ratio, NAFLD fibrosis score(NFS), BARD, Fibrometer test, Fibrotest (FT), Fibrospect-II, PGA-index,PGAA-index, Pohl score, ELF score, SHASTA, Fibrosis probability index(FPI), APRI score, FIB-4 score, and platelet count.
 31. A Method oftreating at least one of NASH and a symptom thereof in a subject in needof treatment thereof comprising administering to said subject apharmaceutical composition comprising at least one of TU, TD, TT, TET,and a combination thereof.
 32. The method of claim 31, wherein saidpharmaceutical composition treats at least one co-morbid condition ofobesity, type 2 diabetes, dyslipidemia, cardiovascular disease, thyroiddysfunction, chronic kidney disease, liver disease, osteoporosis,hypogonadism, hypertension, sarcopenia, and cachexia.
 33. The method ofclaim 31, wherein said pharmaceutical composition is administered withat least one pharmaceutical agent of metformin, glibenclamide,gliclazide, rosiglitazone, pioglitazone, troglitazone, acarbose,miglitol, nateglinide, repaglinide, exenatide, sitagliptin, pramlintide,atorvastatin, rosuvastatin, simvastatin, pravastatin, lovastatin,fluvastatin, pitavastatin, butanoic acid, CER209, evogliptin, DUR928,MK-4074, OPRX-106, PF06865571, PF06882961, PXS-5382A, RG-125, RYI-018,seladelpar, SGM-1019, aramchol, ARX618, BI 1467335, DS102, EDP-305,Emricasan, gemcabene, GR-MD-02, GRI-0621, GS-0976, GS-9674, IMM-124E,IONIS-DGAT2Rx, IVA-337, Lipaglyn, LJN452, LMB763, MGL-3196, MN-001,MSDC-0602K, NC101, NGM282, NS-0200, Ozempic, PF-05221304, PF-06835919,remogliflozin etabonate, SHP626, TVB-2640, VK2809, cenicriviroc,elafibranor, ocaliva (obeticholic acid), selonsertib, and a combinationthereof.
 34. The method of claim 31, wherein if said pharmaceuticalcomposition comprises a single testosterone ester, loading of saidsingle testosterone ester per unit dosage form of said pharmaceuticalcomposition comprises at least one of 1-50% w/w, 5-30% w/w, 10-30% w/w,and 5-15% w/w.
 35. The method of claim 31, wherein if saidpharmaceutical composition comprises a plurality of testosterone estersand includes TU, loading of said TU per unit dosage form of saidpharmaceutical composition comprises at least one of 1-50% w/w, 5-30%w/w, 10-30% w/w, and 5-15% w/w, and wherein if said pharmaceuticalcomposition comprises a plurality of testosterone esters and includesTD, loading of said TD per unit dosage form of said pharmaceuticalcomposition comprises at least one of 1-50% w/w, 5-30% w/w, 10-30% w/w,and 5-15% w/w, and wherein if said pharmaceutical composition comprisesa plurality of testosterone esters and includes TT, loading of said TTper unit dosage form of said pharmaceutical composition comprises atleast one of 1-50% w/w, 5-30% w/w, 10-30% w/w, and 5-15% w/w.
 36. Themethod of claim 31, wherein if said pharmaceutical composition isprepared for a male subject and comprises TU, daily dosage of said TUcomprises at least one of 10 mg to 1,000 mg, 200 mg to 750 mg, and 300mg to 600 mg, and wherein if said pharmaceutical composition is preparedfor a male subject and comprises TD, daily dosage of said TD comprises10 mg to 1,000 mg, and wherein if said pharmaceutical composition isprepared for a male subject and comprises TT, daily dosage of said TTcomprises at least one of 10 mg to 1,000 mg, 400 mg to 2,000 mg, and 600mg to 1,800 mg, and wherein if said pharmaceutical composition isprepared for a female subject and comprises TU, daily dosage of said TUcomprises 1/10th- 1/15th of at least one of 10 mg to 1,000 mg, 200 mg to750 mg, and 300 mg to 600 mg, and wherein if said pharmaceuticalcomposition is prepared for a female subject and comprises TD, dailydosage of said TD comprises 1/10th- 1/15th of 10 mg to 1,000 mg, andwherein if said pharmaceutical composition is prepared for a femalesubject and comprises TT, daily dosage of said TT comprises 1/10th-1/15th of at least one of 10 mg to 1,000 mg, 400 mg to 2,000 mg, and 600mg to 1,800 mg.
 37. The method of claim 31, wherein in response toadministration of said pharmaceutical composition to a male subjecthaving a testosterone concentration baseline below at least one of 350ng/dL, 300 ng/dL, 250 ng/dL, 200 ng/dL, 150 ng/dL, and 100 ng/dL, saidtestosterone concentration (C_(ave0-24)) of said male subject isincreased over said subject's baseline.
 38. The method of claim 37,wherein said testosterone concentration (C_(ave0-24)) increase comprisesan increase of at least one of 30, 50, 75, 100, 150, 200, 300, 400 or500 ng/dL.
 39. The method of claim 31, wherein said pharmaceuticalcomposition comprises at least one pharmaceutically acceptable carrier.40. The method of claim 31, wherein said pharmaceutical compositioncomprises at least one of a hydrophilic carrier, a lipophilic carrier,and an additive.
 41. The method of claim 40, wherein said hydrophiliccarrier comprises at least one of a polyoxylated mono-glyceride, apolyoxylated di-glyceride, a polyoxylated tri-glyceride, a polyoxylatedvegetable oil, a polyoxylated hydrogenated vegetable oil, a polyoxylatedmono-fatty acid, a polyoxylated di-fatty acid, a polyoxylated tri-fattyacid, a hydrogenated vegetable oil, Cremophor, Span, Tween, SLS,Poloxamer, Polymer, and a combination thereof.
 42. The method of claim41, wherein said hydrogenated vegetable oil comprises at least one ofhydrogenated castor oil, hydrogenated coconut oil, hydrogenatedcottonseed oil, hydrogenated palm oil, hydrogenated soybean oil, and acombination thereof.
 43. The method of claim 41, wherein saidpolyoxylated hydrogenated vegetable oil comprises at least one ofpolyoxylated 35 hydrogenated castor oil, polyoxylated 40 hydrogenatedcastor oil and polyoxylated 60 hydrogenated castor oil, and acombination thereof, and wherein said Tween comprises at least one ofTween-20, Tween-21, Tween-40, Tween-60, Tween-61, Tween-65, Tween-80,Tween-81, Tween-85, Tween-120, and a combination thereof.
 44. The methodof claim 40, wherein said lipophilic carrier comprises at least one of avegetable oil, a fatty acid, a fatty alcohol, a mono-glyceride, adi-glyceride, a tri-glyceride, a hydrogenated vegetable oil, a Vitamin Ecompound, polyoxylated fatty acid, polyoxylated triglyceride,polyoxylated vegetable oil, glyceryl fatty acid, propylene glycol fattyacid, a PEG sorbitan fatty acid esters, a omega-3 fatty acid, a PEGglycol alkyl ether, a polyglycerized fatty acid, and a combinationthereof.
 45. The method of claim 44, wherein said vegetable oilcomprises at least one of castor oil, coconut oil, borage oil,cottonseed oil, peppermint oil, corn oil, peanut oil, linseed oil, oliveoil, palm oil, sesame oil, soybean oil, and a combination thereof. 46.The method of claim 44, wherein said fatty acid comprises at least oneof caprylic acid, capric acid, lauric acid, palmitic acid, stearic acid,arachidic acid, behenic acid, myristoleic acid, palmitoleic acid,sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid,linoelaidic acid, and a combination thereof, and wherein said omega-3fatty acid comprises at least one of omega-3 EPA, omega-3 DHA, and acombination thereof.
 47. The method of claim 44, wherein saidhydrogenated vegetable oil comprises at least one of hydrogeneatedcastor oil, hydrogeneated coconut oil, hydrogeneated cottonseed oil,hydrogenated palm oil, hydrogenated soybean oil, and a combinationthereof.
 48. The method of claim 44, wherein said glyceryl fatty acidcomprises at least one of glyceryl stearate, glyceryl oleate, glycerylcaprate, glyceryl caprylate, glyceryl laurate, glyceryl stearate,glyceryl palmitate, glyceryl linoleate, glyceryl myristate, and acombination thereof, and wherein said propylene glyceryl fatty acidcomprises at least one of propylene glyceryl stearate, propyleneglyceryl oleate, propylene glyceryl caprate, propylene glycerylcaprylate, propylene glyceryl laurate, propylene glyceryl stearate,propylene glyceryl palmitate, propylene glyceryl ricinoleate, propyleneglyceryl myristate, and a combination thereof.
 49. The method of claim48, wherein said glyceryl fatty acid comprises at least one of aglyceryl mono-fatty acid, a glyceryl di-fatty acid, and a glyceryltri-fatty acid, and wherein said propylene glyceryl fatty acid comprisesat least one of a propylene glyceryl mono-fatty acid, a propyleneglyceryl di-fatty acid, and a propylene glyceryl tri-fatty acid.
 50. Themethod of claim 31, wherein said method further includes administering atherapeutically effective amount of a combination of androgen receptoragonists to said subject.
 51. The method of claim 31, wherein saidsubject has at least one co-morbid condition selected from obesity, type2 diabetes, dyslipidemia, cardiovascular disease, thyroid dysfunction,chronic kidney disease, liver disease, osteoporosis, hypogonadism,hypertension, sarcopenia, and cachexia.
 52. The method of claim 31,wherein said subject comprises at least one of a post-transplantationsubject, pending transplantation subject, a transplantation rejectionsubject, and a combination thereof.
 53. The method of claim 31, whereinsaid treatment results in improvement or amelioration of changes in bodycomposition, muscle mass, appendicular lean mass, total lean mass, fatmass, high VAT (visceral adipose fat), waist circumference, weight gain,BMI, mobility/frailty, hand grip strength, liver frailty index, balance,and chair stand ability, and a patient reported outcome (PRO).
 54. Themethod of claim 53, wherein said PRO comprises at least one of afunctional status of patient-COA-symptom only known to said patient, aquality of life (QOL) assessed by CLDQ, a perceived HRQoL score,depression, degree of mobility, sexual dysfunction, and FIS fatiguequestionnaire.
 55. The method of claim 31, wherein said treatmentresults in improvement or amelioration of at least one biomarkercomprising a liver injury marker, lipoprotein-associated phospholipaseA2, triglyceride, LDL, total cholesterol, cholesterol, hematocrit,hemoglobin, albumin, VLDL, non-HDL, SHBG, an imaging biomarker, liverstiffness, liver biopsy, inflammation, fibrosis, bilirubin, and a liverhistology biomarker.
 56. The method of claim 55, wherein said liverinjury marker comprises at least one of ALT, AST, ALP, and GGT, andwherein said fibrosis biomarker comprises at least one of CK18, AST/ALTratio, NAFLD fibrosis score (NFS), BARD, Fibrometer test, Fibrotest(FT), Fibrospect-II, PGA-index, PGAA-index, Pohl score, ELF score,SHASTA, Fibrosis probability index (FPI), APRI score, FIB-4 score, andplatelet count.
 57. The method of claim 31, wherein said administeringcomprises an oral administration.